Microglia and synapses
Cunningham C, Deacon R, Wells H, Boche D, Waters S, Diniz CP,
Scott H, Rawlins JN, Perry VH (2003) Synaptic changes characterize
early behavioural signs in the ME7 model of murine prion disease.
Eur.J.Neurosci. 17:2147-2155
Abstract: Prion diseases are fatal,
chronic neurodegenerative diseases of mammals, characterized by
amyloid deposition, astrogliosis, Microglial
activation, tissue vacuolation and neuronal loss. In the ME7 model
of prion disease in the C57BL/6 J mouse, we have shown previously
that these animals display behavioural changes that indicate the
onset of neuronal dysfunction. The current study examines the
neuropathological correlates of these early behavioural changes.
After injection of ME7-infected homogenate into the dorsal
hippocampus, we found statistically significant impairment of
burrowing, nesting and glucose consumption, and increased open field
activity at 13 weeks. At this time, Microglia
activation and PrPSc deposition was visible selectively throughout
the limbic system, including the hippocampus, entorhinal cortex,
medial and lateral septum, mamillary bodies, dorsal thalamus and, to
a lesser degree, in regions of the brainstem. No increase in
apoptosis or neuronal cell loss was detectable at this time, while
in animals at 19 weeks postinjection there was 40% neuronal loss
from CA1. There was a statistically significant reduction in
synaptophysin staining in the stratum radiatum of the CA1 at 13
weeks indicating loss of presynaptic terminals. Damage to the dorsal
hippocampus is known to disrupt burrowing and nesting behaviour. We
have demonstrated a neuropathological correlate of an early
behavioural deficit in prion disease and suggest that this should
allow insights into the first steps of the neuropathogenesis of
prion diseases
Hansson E, Ronnback L (2003) Glial neuronal signaling in the
central nervous system. FASEB J. 17:341-348
Abstract: Glial cells
are known to interact extensively with neuronal elements in the
brain, influencing their activity. Astrocytes associated with
synapses integrate neuronal
inputs and release transmitters that modulate synaptic sensitivity.
Glial cells participate in formation and rebuilding of synapses
and play a prominent role in protection and repair of nervous tissue
after damage. For glial cells to take an active part in plastic
alterations under physiological conditions and pathological
disturbances, extensive specific signaling, both within single cells
and between cells, is required. In recent years, intensive research
has led to our first insight into this signaling. We know there are
active connections between astrocytes in the form of networks
promoting Ca2+ and ATP signaling; we also know there is intense
signaling between astrocytes, Microglia,
oligodendrocytes, and neurons, with an array of molecules acting as
signaling substances. The cells must be functionally integrated to
facilitate the enormous dynamics of and capacity for reconstruction
within the nervous system. In this paper, we summarize some basic
data on glial neuronal signaling to provide insight into synaptic
modulation and reconstruction in physiology and protection and
repair after damage
Li Y, Liu L, Barger SW, Griffin WS (2003) Interleukin-1
mediates pathological effects of Microglia
on tau phosphorylation and on synaptophysin synthesis in cortical
neurons through a p38-MAPK pathway. J.Neurosci.
23:1605-1611
Abstract: The presence of tangles of abnormally
phosphorylated tau is a characteristic of Alzheimer's disease (AD),
and the loss of synapses
correlates with the degree of dementia. In addition, the
overexpression of interleukin-1 (IL-1) has been implicated in tangle
formation in AD. As a direct test of the requirement for IL-1 in tau
phosphorylation and synaptophysin expression, IL-1 actions in
neuron-Microglia
cocultures were manipulated. Activation of Microglia
with secreted beta-amyloid precursor protein or lipopolysaccharide
elevated their expression of IL-1alpha, IL-1beta, and tumor necrosis
factor alpha (TNFalpha) mRNA. When such activated Microglia
were placed in coculture with primary neocortical neurons, a
significant increase in the phosphorylation of neuronal tau was
accompanied by a decline in synaptophysin levels. Similar effects
were evoked by treatment of neurons with recombinant IL-1beta. IL-1
receptor antagonist (IL-1ra) as well as anti-IL-1beta antibody
attenuated the influence of activated Microglia
on neuronal tau and synaptophysin, but anti-TNFalpha antibody was
ineffective. Some effects of Microglial
activation on neurons appear to be mediated by activation of p38
mitogen-activated protein kinase (p38-MAPK), because activated
Microglia
stimulated p38-MAPK phosphorylation in neurons, and an inhibitor of
p38-MAPK reversed the influence of IL-1beta on tau phosphorylation
and synaptophysin levels. Our results, together with previous
observations, suggest that activated Microglia
may contribute to neurofibrillary pathology in AD through their
production of IL-1, activation of neuronal p38-MAPK, and resultant
changes in neuronal cytoskeletal and synaptic elements
Liu PH, Wang YJ, Tseng GF (2003) Close axonal injury of
rubrospinal neurons induced transient perineuronal astrocytic and
Microglial
reaction that coincided with their massive degeneration. Exp.Neurol.
179:111-126
Abstract: To learn more about the pathophysiology of
axonal injury and the significance of axon collaterals on the
survival of axotomized cord-projection central neurons, we studied
the survival rate, surrounding astrocytic and Microglial
reactions, and bouton coverage on rat rubrospinal cell bodies
following their axonal lesion at the brain stem and upper cervical
level. The brain stem lesion disconnected most rubrospinal neurons
from all their targets, while the upper cervical lesion spared their
supraspinal collaterals. Much higher cell loss accompanied by robust
astrocytic and Microglial
reaction was found following brain stem than upper cervical lesion
starting 4 days postaxotomy. The reaction of astrocytes had subsided
while Microglial
reaction remained relatively robust by 10 weeks postaxotomy when the
cell loss had slowed down. Ultrastructural observation revealed that
reactive astrocytes covered 40%, an increase from the 20% of
control, of brain stem-axotomized rubrospinal cell body surface at 4
days and 2 weeks and returned to normal levels by 10 weeks
postlesion. An increase of apposition by axons and dendrites and a
moderate decrease of round and flattened vesicle-containing bouton
contacts at 4 days and 2 weeks and returning to normal levels at 10
weeks postaxotomy accompanied this. It appears that although axotomy
induced robust astrocytic reaction around cord-projection central
neurons, this, unlike their periphery-projection counterparts,
failed to effectively strip their somatic synapses.
In effect, this might in part determine neuronal fate following
axonal injury
Tripanichkul W, Stanic D, Drago J, Finkelstein DI, Horne MK
(2003) D2 Dopamine receptor blockade results in sprouting of DA
axons in the intact animal but prevents sprouting following nigral
lesions. Eur.J.Neurosci. 17:1033-1045
Abstract: Recently it was
demonstrated that sprouting of dopaminergic neurons and a Microglial
and astrocyte response follows both partial lesions of the
substantia nigra pars compacta and blockade of the D2 dopamine
receptor. We therefore studied the effects of the combination of
these two treatments (lesioning and D2 dopamine receptor blockade).
Haloperidol administration caused a 57% increase in dopaminergic
terminal tree size (measured as terminal density per substantia
nigra pars compacta neuron) and an increase of glia in the striatum.
Following small to medium nigral lesions (less than 60%), terminal
tree size increased by 51% on average and returned density of
dopaminergic terminals to normal. In contrast, administration of
haloperidol for 16 weeks following lesioning resulted in reduced
dopaminergic terminal density and terminal tree size (13%),
consistent with absent or impaired sprouting. Glial cell numbers
increased but were less than with lesions alone. When haloperidol
was administered after the striatum had been reinnervated through
sprouting (16-32 weeks after lesioning), terminal tree size
increased up to 150%, similar to the effect of haloperidol in normal
animals. By examining the effect of administering haloperidol at
varying times following a lesion, we concluded that a switch in the
effect of D2 dopamine receptor blockade occurred after dopaminergic
synapses began to form in
the striatum. We postulate that when synapses
are present, D2 dopamine receptor blockade results in increased
terminal density, whereas prior to synapse
formation D2 dopamine receptor blockade causes attenuation of a
sprouting response. We speculate that D2 dopamine receptors located
on growth cones 'push' neurites toward their targets, and blockade
of these receptors could lead to attenuation of sprouting
Tropea D, Caleo M, Maffei L (2003) Synergistic effects of
brain-derived neurotrophic factor and chondroitinase ABC on retinal
fiber sprouting after denervation of the superior colliculus in
adult rats. J.Neurosci. 23:7034-7044
Abstract: Damage to the
adult CNS often causes devastating and permanent deficits because of
the limited capacity of the brain for anatomical reorganization. The
finding that collateral sprouting of uninjured fiber tracts mediates
recovery of function prompts the search for experimental strategies
that stimulate axonal plasticity after CNS trauma. Here we
characterize treatments that promote the sprouting of undamaged
retinal afferents into the denervated superior colliculus (SC) after
a partial retinal lesion in the adult rat. Delivery of brain-derived
neurotrophic factor (BDNF) was performed to enhance the intrinsic
potential of retinal ganglion cells to reelongate their axons.
Reduction of the neurite growth-inhibitory properties of the adult
SC was accomplished via treatment with chondroitinase ABC (C-ABC),
which degrades chondroitin sulfate proteoglycans. Retinal axons were
labeled via intraocular injections of fluorescently tagged cholera
toxin B subunit, and fiber sprouting within the denervated SC was
measured by quantitative laser-scanning confocal microscopy 1 week
after the retinal lesion. We found that both the administration of
BDNF and the injection of C-ABC induce significant sprouting of
retinal afferents into the collicular scotoma. Remarkably, the
combined treatment with BDNF and C-ABC showed synergistic effects on
axon growth. Colocalization analysis with anti-synapsin
antibodies demonstrated synapse
formation by the sprouting axons. These results suggest that the
combined treatment with BDNF and C-ABC can be relevant in therapies
for the repair of the damaged adult CNS
Andreoletti O, Berthon P, Levavasseur E, Marc D, Lantier F,
Monks E, Elsen JM, Schelcher F (2002) Phenotyping of protein-prion
(PrPsc)-accumulating cells in lymphoid and neural tissues of
naturally scrapie-affected sheep by double-labeling
immunohistochemistry. J.Histochem.Cytochem. 50:1357-1370
Abstract:
Transmissible spongiform encephalopathies are fatal
neurodegenerative diseases characterized by amyloid deposition of
protein-prion (PrPsc), the pathogenic isoform of the host cellular
protein PrPc, in the immune and central nervous systems. In the
absence of definitive data on the nature of the infectious agent,
PrPsc immunohistochemistry (IHC) constitutes one of the main
methodologies for pathogenesis studies of these diseases. In situ
PrPsc immunolabeling requires formalin fixation and paraffin
embedding of tissues, followed by post-embedding antigen retrieval
steps such as formic acid and hydrated autoclaving treatments. These
procedures result in poor cellular antigen preservation, precluding
the phenotyping of cells involved in scrapie pathogenesis. Until
now, PrPsc-positive cell phenotyping relied mainly on morphological
criteria. To identify these cells under the PrPsc IHC conditions, a
new, rapid, and highly sensitive PrPsc double-labeling technique was
developed, using a panel of screened antibodies that allow specific
labeling of most of the cell subsets and structures using
paraffin-embedded lymphoid and neural tissues from sheep, leading to
an accurate identification of ovine PrPsc-accumulating cells. This
technique constitutes a useful tool for IHC investigation of scrapie
pathogenesis and may be applicable to the study of other ovine
infectious diseases
Bi X, Gall CM, Zhou J, Lynch G (2002) Uptake and pathogenic
effects of amyloid beta peptide 1-42 are enhanced by integrin
antagonists and blocked by NMDA receptor antagonists. Neuroscience
112:827-840
Abstract: Many synapses
contain two types of receptors - integrins and N-methyl-D-aspartate
(NMDA) receptors - that have been implicated in peptide
internalization. The present studies tested if either class is
involved in the uptake of the 42-residue form of amyloid beta
peptide (Abeta1-42), an event hypothesized to be of importance in
the development of Alzheimer's disease. Cultured hippocampal slices
were exposed to Abeta1-42 for 6 days in the presence or absence of
soluble Gly-Arg-Gly-Asp-Ser-Pro, a peptide antagonist of Arg-Gly-Asp
(RGD)-binding integrins, or the disintegrin echistatin. Abeta
uptake, as assessed with immunocytochemistry, occurred in 42% of the
slices incubated with Abeta peptide alone but in more than 80% of
the slices co-treated with integrin antagonists. Uptake was also
found in a broader range of hippocampal subfields in RGD-treated
slices. Increased sequestration was accompanied by two
characteristics of early stage Alzheimer's disease: elevated
concentrations of cathepsin D immunoreactivity and activation of
Microglia.
The selective NMDA receptor antagonist
D-(-)-2-amino-5-phosphonovalerate completely blocked internalization
of Abeta, up-regulation of cathepsin D, and activation of Microglia.
Our results identify two classes of receptors that cooperatively
regulate the internalization of Abeta1-42 and support the hypothesis
that characteristic pathologies of Alzheimer's disease occur once
critical intraneuronal Abeta concentrations are reached
Ferrer I (2002) Synaptic pathology and cell death in the
cerebellum in Creutzfeldt-Jakob disease. Cerebellum.
1:213-222
Abstract: Prion protein (PrP(c)) is a cell membrane
glycoprotein particularly abundant in the synapses.
Prion diseases are characterized by the replacement of the normal
PrPc by a protease-resistant, sheet-containing isoform (PrP(CJD),
PrP(Sc), PrP(BSE)) that is pathogenic. Creutzfeldt-Jakob disease
(CJD) in humans, scrapie (Sc) in sheep and goats, and bovine
spongiform encephalopathy (BSE) in cattle are typical prion
diseases. Classical CJD can be presented as sporadic, infectious or
familial, whereas the new variant of CJD (nvCJD) is considered a
BSE-derived human disease. Spongiform degeneration, glial
proliferation, involving astrocytes and Microglia,
neuron loss and abnormal PrP deposition are the main
neuopathological findings in most human and animal prion diseases.
Yet recent data point to synapses
as principal targets of abnormal PrP deposition. Loss of synapses
is an early abnormality in experimental scrapie. Decreased
expression of crucial proteins linked to exocytosis and
neurotransmission, covering synaptophysin, synaptosomal-associated
protein of 25,000 mol wt (SNAP-25), synapsins,
syntaxins and Rab3a occurs in the cerebral cortex and cerebellum in
sporadic CJD. Moreover, impairment of glomerular synapses
and attenuation of parallel fiber pre-synaptic terminals on Purkinje
cell dendrites is a cardinal consequence of abnormal PrP metabolism
in CJD. Accumulation of synaptic proteins in the soma and axonal
torpedoes of Purkinje cells suggests additional impairment of axonal
transport. Increase in nuclear DNA vulnerability leading to
augmented numbers of cells bearing nuclear DNA fragments is a common
feature in the brains of humans affected by prion diseases examined
at post-mortem, but also in archival biopsy samples processed with
the method of in situ end-labeling of nuclear DNA fragmentation.
This form of cell death is reminiscent of apoptosis found in
experimental scrapie in rodents. It is not clear that all forms of
cell death in human and animal prion diseases are due to apoptosis.
Yet new observations have shown cleaved (active) caspase-3 (17 kDa),
a main executioner of apoptosis, expressed in scattered cells in the
brains of mice with experimental scrapie and in the cerebellum of
patients with sporadic CJD. Together, these data suggest activation
of the caspase pathway of apoptosis in human and animal prion
diseases
Fields RD, Stevens-Graham B (2002) New insights into
neuron-glia communication. Science 298:556-562
Abstract: Two-way
communication between neurons and nonneural cells called glia is
essential for axonal conduction, synaptic transmission, and
information processing and thus is required for normal functioning
of the nervous system during development and throughout adult life.
The signals between neurons and glia include ion fluxes,
neurotransmitters, cell adhesion molecules, and specialized
signaling molecules released from synaptic and nonsynaptic regions
of the neuron. In contrast to the serial flow of information along
chains of neurons, glia communicate with other glial cells through
intracellular waves of calcium and via intercellular diffusion of
chemical messengers. By releasing neurotransmitters and other
extracellular signaling molecules, glia can affect neuronal
excitability and synaptic transmission and perhaps coordinate
activity across networks of neurons
Hauss-Wegrzyniak B, Lynch MA, Vraniak PD, Wenk GL (2002)
Chronic brain inflammation results in cell loss in the entorhinal
cortex and impaired LTP in perforant path-granule cell synapses.
Exp.Neurol. 176:336-341
Abstract: Alzheimer's disease (AD) is
characterized by chronic neuroinflammation, significant temporal
lobe cell loss, and dementia. We investigated the influence of
chronic neuroinflammation produced by chronic infusion of
lipopolysaccharide (LPS) into the fourth ventricle for 4 weeks upon
the induction and maintenance of long-term potentiation (LTP) in the
dentate gyrus of the hippocampus, a well-characterized model of
cellular synaptic plasticity. We also examined for pyramidal cell
loss within the entorhinal cortex an area of the brain that contains
the cell bodies of the perforant path. The results demonstrate that
chronic neuroinflammation results in the loss of pyramidal cells
within layers II and III of the entorhinal cortex and a significant
attenuation of LTP within the dentate gyrus. Similar changes may
underlie the temporal lobe pathology and dementia associated with AD
Peters A, Sethares C (2002) The effects of age on the cells
in layer 1 of primate cerebral cortex. Cereb.Cortex
12:27-36
Abstract: Although there is significant thinning of
layer 1 with age in both occipital area 17 and prefrontal area 46 of
the rhesus monkey, there are no significant age-related changes in
the numbers of neurons, astrocytes, or Microglia
and oligodendrocytes in this layer. A few profiles of degenerating
neurons have been encountered in old monkeys, but they are uncommon.
Some astrocytes undergo hypertrophy with age, as evidenced by the
increased thickness of the glial limiting membrane, and throughout
layer 1 the amount of filaments in the cytoplasm of both their cell
bodies and processes increases. The astrocytes also come to contain
phagocytic material in the old monkeys, as do the Microglial
cells. We have previously shown that in both areas 17 and 46 there
is an age-related loss of synapses
from layer 1 and a concomitant loss of dendritic branches from the
apical tufts of pyramidal cells from layer 1. These may be the
sources of the material phagocytosed by the astrocytes and
Microglial
cells
Peters A (2002) Structural changes that occur during normal
aging of primate cerebral hemispheres. Neurosci.Biobehav.Rev.
26:733-741
Abstract: Human and non-human primates show cognitive
decline during normal aging. Originally, the decline was attributed
to a loss of cortical neurons, but recent studies have shown there
is no significant cortical neuronal loss with age. Neurons acquire
pigment, but the only other obvious changes are in layer 1 of
neocortex. Layer 1 becomes thinner as apical tufts of pyramidal
cells lose branches, as well as synapses,
and at the same time the glial limiting membrane thickens. How
dendrites and synapses in
deep layers are affected by age is uncertain, but there are
decreases in the levels of some neurotransmitters and receptors.
Throughout the brain myelin sheaths show signs of breakdown. This
may contribute to cognitive decline because it would cause a slowing
of conduction along nerve fibers, disrupting the timing in neuronal
circuits. Concomitantly, the myelin-forming oligodendrocytes develop
swellings along their processes and gain dense inclusions.
Microglial
cells and astrocytes accumulate large amounts of phagocytosed
material with age, although the origins of this material are not
known
Peters A (2002) Structural changes in the normally aging
cerebral cortex of primates. Prog.Brain Res. 136:455-465
Abstract:
During normal aging humans exhibit some cognitive decline, but it is
difficult to determine the underlying causes of this decline,
because information about cognitive status is rarely available and
preservation of the brain is usually inadequate for detailed
cytological examination. One solution to this problem is to use a
nonhuman primate model, such as the rhesus monkey, which exhibits
age-related cognitive decline similar to humans, and can be
cognitively tested before the brains are preserved for detailed
examination. It is now known that cognitive decline in human and
nonhuman primates is not due to loss of cortical neurons and there
is no correlation between the frequency of senile plaques and
cognitive status. Indeed apart from layer 1, neurons of cerebral
cortex show few signs of aging, although there may be some loss of
synapses throughout cortex.
In contrast, both Microglia
and astrocytes come to contain phagocytosed material, but its origin
is unknown. There is also loss of white matter, which is accompanied
by some breakdown of myelin sheaths and alterations in
oligodendrocytes. It is suggested that the myelin changes alter
conduction velocities along axons. This would alter timing in
neuronal circuits, contributing to cognitive decline
Siso S, Puig B, Varea R, Vidal E, Acin C, Prinz M, Montrasio
F, Badiola J, Aguzzi A, Pumarola M, Ferrer I (2002) Abnormal
synaptic protein expression and cell death in murine scrapie. Acta
Neuropathol.(Berl) 103:615-626
Abstract: Reduced expression of
synaptophysin p38, synaptic-associated protein of molecular weight
25,000 (SNAP-25), syntaxin-1, synapsin-1,
and alpha- and beta-synuclein, matching the distribution of
spongiform degeneration, was found in the neurological phase of
scrapie-infected mice. In addition, synaptophysin and SNAP-25 were
accumulated in isolated neurons, mainly in the thalamus, midbrain
and pons, and granular deposits of alpha- and beta-synuclein were
present in the neuropil of the same areas. No modifications in the
steady state levels of Bcl-2, Bax, Fas and Fas ligand were observed
following infection. Yet antibodies against the c-Jun N-terminal
peptide, which cross-react with products emerging after
caspase-mediate proteolysis, recognize coarse granular deposits in
the cytoplasm of reactive Microglia.
In situ end-labeling of nuclear DNA fragmentation showed positive
nuclei with extreme chromatin condensation in the thalamus, pons,
hippocampus and, in particular, the granular layer of the
cerebellum. More importantly, expression of cleaved caspase-3, a
major executioner of apoptosis, was seen in a few cells in the same
regions, thus indicating that cell death by apoptosis in
scrapie-infected mice is associated with caspase-3 activation. The
present findings support the concept that synaptic pathology is a
major substrate of neurological impairment and that caspase-3
activation may play a pivotal role in apoptosis in experimental
scrapie. However, there is no correlation between decreased synaptic
protein expression and caspase-3-associated apoptosis, which
suggests that in addition to abnormal prion protein deposition,
there may be other factors that distinctively influence synaptic
vulnerability and cell death in murine scrapie
Barger SW, Basile AS (2001) Activation of Microglia
by secreted amyloid precursor protein evokes release of glutamate by
cystine exchange and attenuates synaptic function. J.Neurochem.
76:846-854
Abstract: Microglial
activation as part of a chronic inflammatory response is a prominent
component of Alzheimer's disease. Secreted forms of the beta-amyloid
precursor protein (sAPP) previously were found to activate
Microglia,
elevating their neurotoxic potential. To explore neurotoxic
mechanisms, we analyzed Microglia-conditioned
medium for agents that could activate glutamate receptors.
Conditioned medium from primary rat Microglia
activated by sAPP caused a calcium elevation in hippocampal neurons,
whereas medium from untreated Microglia
did not. This response was sensitive to the NMDA receptor
antagonist, aminophosphonovaleric acid. Analysis of
Microglia-conditioned
by HPLC revealed dramatically higher concentrations of glutamate in
cultures exposed to sAPP. Indeed, the glutamate levels in
sAPP-treated cultures were substantially higher than those in
cultures treated with amyloid beta-peptide. This sAPP-evoked
glutamate release was completely blocked by inhibition of the
cystine-glutamate antiporter by alpha-aminoadipate or use of
cystine-free medium. Furthermore, a sublethal concentration of sAPP
compromised synaptic density in Microglia-neuron
cocultures, as evidenced by neuronal connectivity assay. Finally,
the neurotoxicity evoked by sAPP in Microglia-neuron
cocultures was attenuated by inhibitors of either the neuronal
nitric oxide synthase (N(G)-propyl-L-arginine) or inducible nitric
oxide synthase (1400 W). Together, these data indicate a scenario by
which Microglia
activated by sAPP release excitotoxic levels of glutamate, probably
as a consequence of autoprotective antioxidant glutathione
production within the Microglia,
ultimately causing synaptic degeneration and neuronal death
DeFelipe J, Segura T, Arellano JI, Merchan A,
DeFelipe-Oroquieta J, Martin P, Maestu F, Cajal S, Sanchez A, Sola
RG (2001) Neuropathological findings in a patient with epilepsy and
the Parry-Romberg syndrome. Epilepsia 42:1198-1203
Abstract:
PURPOSE: The Parry-Romberg syndrome is an unusual disorder
frequently associated with epilepsy. The origin of this disease, and
the cause of epilepsy, are unknown. This study is the first reported
case of the Parry-Romberg syndrome, with intractable temporal lobe
epilepsy, in which detailed microanatomic analyses have been
performed on resected brain tissue obtained after surgical
intervention. METHODS: Standard histopathologic methods and
correlative light and electron microscopy, combined with
immunocytochemical techniques, were used to study in detail the
synaptic microorganization of the resected hippocampal formation.
RESULTS: After surgery, the patient was seizure free (follow-up
period of 4 years and 7 months). The resected temporal lobe showed a
variety of dramatic microanatomic alterations (small groups of
ectopic cells, neuronal loss, gliosis, and activated Microglial
cells) in mesial structures, including the entorhinal cortex,
subiculum, and dentate gyrus. At the electron-microscopic level, we
found that in the dentate gyrus, the number of synapses
in the cell-sparse region adjacent to the ectopic mass of neurons
was almost twice that found in the molecular and polymorph cell
layers, indicating the intrusion of neuritic processes and synapse
formation. In addition, the symmetrical axosomatic synapses
characteristically found on granule cells, which are likely derived
from gamma-aminobutyric acid (GABA)ergic inhibitory basket cells,
were not observed. CONCLUSION: The complete seizure relief after
surgery suggests that the pacemaker region(s) of seizure activity
were within the resected tissue. However, we do not know which of
the multiple neuropathologic findings reported here were the primary
cause of seizure activity. Nevertheless, the changes found in the
dentate gyrus circuitry appear to be among the most important
alterations that would lead to epilepsy
Gerecke KM, Wyss JM, Karavanova I, Buonanno A, Carroll SL
(2001) ErbB transmembrane tyrosine kinase receptors are
differentially expressed throughout the adult rat central nervous
system. J.Comp Neurol. 433:86-100
Abstract: The neuregulin (NRG)
family of growth and differentiation factors and their erbB
receptors contribute importantly to the development of the nervous
system, but their distribution and function in the adult brain are
poorly understood. The present study showed that erbB2, erbB3, and
erbB4 transcripts and protein are distributed throughout all areas
of adult rat brain. These three receptors were differentially
expressed in neurons and glia. Some neurons expressed only a subset
of erbB kinases, whereas other neurons expressed all three erbB
receptors but sequestered each of these polypeptides into distinct
cellular compartments. In synapse-rich
regions, erbB immunoreactivity appeared as punctate-, axon-, and/or
dendrite-associated staining, suggesting that NRGs are involved in
the formation and maintenance of synapses
in adult brain. ErbB labeling also was present in neuronal soma,
indicating that NRGs act at sites in addition to the synapse.
Glia in adult brain also differentially expressed erbB3 and erbB4.
Approximately half of the erbB3 labeling in white matter was
associated with S100beta+/glial fibrillary acidic protein negative
macroglia (i.e., oligodendrocytes or glial fibrillary acidic protein
negative astrocytes). In contrast, macroglia in gray matter did not
express erbB3. The remaining erbB3 immunoreactivity in white matter
and erbB4 glial staining seemed to be associated with Microglia.
These results showed that erbB receptors are expressed widely in
adult rat brain and that each erbB receptor subtype has a distinct
distribution. The differential distributions of erbB receptors in
neurons and glia and the known functional differences between these
kinases suggest that NRGs have distinct effects on these cells. The
continued expression of NRGs and their erbB receptors in mature
brain also implies that these molecules perform important functions
in the brain throughout life
James G, Butt AM (2001) Changes in P2Y and P2X purinoceptors
in reactive glia following axonal degeneration in the rat optic
nerve. Neurosci.Lett. 312:33-36
Abstract: Purinoceptors have been
shown to be important in mediating Ca(2+) signalling in glial cells
and it has been proposed that they may have a role in their response
to injury. To investigate this, the glial response to adenosine
5'triphosphate (ATP) was measured in situ, in optic nerves from
juvenile rats that were enucleated at postnatal day (P) 1;
age-matched normal nerves were used as controls. The optic nerve is
a typical central nervous system (CNS) white matter tract containing
axons and glial cells, but not neurones or synapses.
Following neonatal enucleation, axons degenerate and
oligodendrocytes do not develop, so that the optic nerve is
populated predominantly by reactive astrocytes, with a minor
population of activated Microglia.
Application of 1 mM ATP evoked a large and rapid increase in glial
[Ca(2+)](i) in fura-2 ratiometric whole nerve recordings from normal
and gliotic axon-free nerves. Significantly, the response to ATP had
a prolonged duration in gliotic axon-free nerves and there was as
shift in the agonist rank order of potency from ATP = ADP > UTP
>> alpha,beta-metATP to ATP > ADP = UTP =
alpha,beta-metATP. The results indicate an in situ role for ATP
signalling in reactive astrocytes, via metabotropic P2Y(1) and
P2Y(2/4) purinoceptors and ionotropic P2X purinoreceptors. The
change in the purinoceptor profile following axon degeneration
suggests a special role for P2X purinoceptors in mediating the glial
reaction to CNS injury
Kalla R, Liu Z, Xu S, Koppius A, Imai Y, Kloss CU, Kohsaka S,
Gschwendtner A, Moller JC, Werner A, Raivich G (2001) Microglia
and the early phase of immune surveillance in the axotomized facial
motor nucleus: impaired Microglial
activation and lymphocyte recruitment but no effect on neuronal
survival or axonal regeneration in macrophage-colony stimulating
factor-deficient mice. J.Comp Neurol. 436:182-201
Abstract:
Activation of Microglia
is among the first cellular changes in the injured CNS. However,
little is known about their specific contribution to secondary
damage or repair processes in neighboring neurons and nonneuronal
cells or to the immune surveillance of the damaged tissue. Animal
models with defective Microglial
response such as osteopetrosis provide an approach to explore these
effects. Osteopetrosis (op) is an autosomal recessive mutation with
a complete deficiency of the macrophage-colony stimulating factor
(MCSF; CSF-1), an important mitogen for brain Microglia.
In the current study we examined the effects of this MCSF deficiency
on the Microglial
reaction and the overall cellular response to nerve injury in the
mouse axotomized facial motor nucleus. In the brain, MCSF receptor
immunoreactivity was found only on Microglia
and was strongly up-regulated following injury. MCSF deficiency led
to a failure of Microglia
to show a normal increase in early activation markers
(thrombospondin, MCSF receptor, alpha M beta 2- and alpha 5 beta
1-integrins), to spread on the surface of axotomized motoneurons,
and to proliferate after injury. Early recruitment of CD3(+)
T-lymphocytes to the facial nucleus 24 hours after injury was
reduced by 60%. In contrast, the neuronal and astrocyte response was
not affected. There was a normal increase in the neuropeptides
calcitonin gene-related peptide and galanin, neuronal c-JUN, and
NADPH-diaphorase and a decrease in choline acetyltransferase and
acetylcholinesterase. Astrocyte glial fibrillary acidic protein
immunoreactivity also showed a normal increase. There was a normal
influx of macrophages and granulocytes into the injured facial
nerve. Synaptic stripping, neuronal survival, and speed of axonal
regeneration were also not affected. The current results show a
strong, selective effect of MCSF on the early activation of
Microglia
and, indirectly, on lymphocyte recruitment. This early phase of
Microglial
activation appears not to be involved in the process of repair
following peripheral nerve injury. However, it is important in the
initiation of inflammatory changes in the brain and in the
interaction with the immune system
Nomura H, Furuta A, Suzuki SO, Iwaki T (2001) Dorsal horn
lesion resulting from spinal root avulsion leads to the accumulation
of stress-responsive proteins. Brain Res. 893:84-94
Abstract: The
aim of this study was to demonstrate acute to subacute molecular
episodes in the dorsal horn following root avulsion using
immunohistochemical methods with the markers for synapses,
astrocytes and such stress-responsive molecules as heat shock
proteins (Hsps) and p38 MAP kinase (p38). Among them, Hsp27 was
accumulated selectively in the injured substantia gelatinosa 24 h
after avulsion injury. The localization of Hsp27 in astrocytes
within the substantia gelatinosa was confirmed by the double
immunofluorescence method using anti-Hsp27 antibody and either
anti-synaptophysin antibody or anti-glutamine synthetase antibody
and by immunoelectron microscopy for Hsp27. The pattern of Hsp27
expression subsequently changed from glial pattern to punctate
pattern by 7 days. Immunoelectron microscopy revealed that the
punctate pattern in the subacute stage corresponded to distal parts
of the astrocytic processes. Hsp27 immunoreaction was decreased 21
days after root avulsion. In the distal axotomy model, Hsp27 was
accumulated later in the ipsilateral dorsal horn in a punctate
pattern from 7 days after the axotomy. Phosphorylation of p38 was
detected in Microglia
in the dorsal horn following both avulsion and axotomy. Substance P
was slightly decreased in the injured substantia gelatinosa in both
the avulsion and axotomy models around 14-21 days. We conclude that
Hsp27 is a useful marker for demonstrating dorsal horn lesions
following avulsion injury and that avulsion injury may induce Hsp27
in the dorsal horn more rapidly than distal axotomy
Wegiel J, Wang KC, Imaki H, Rubenstein R, Wronska A,
Osuchowski M, Lipinski WJ, Walker LC, LeVine H (2001) The role of
Microglial
cells and astrocytes in fibrillar plaque evolution in transgenic
APP(SW) mice. Neurobiol.Aging 22:49-61
Abstract: Ultrastructural
reconstruction of 27 fibrillar plaques in different stages of
formation and maturation was undertaken to characterize the
development of fibrillar plaques in the brains of human APP(SW)
transgenic mice (Tg2576). The study suggests that Microglial
cells are not engaged in Abeta removal and plaque degradation, but
in contrast, are a driving force in plaque formation and
development. Fibrillar Abeta deposition at the amyloid pole of
Microglial
cells appears to initiate three types of neuropil response:
degeneration of neurons, protective activation of astrocytes, and
attraction and activation of Microglial
cells sustaining plaque growth. Enlargement of neuronal processes
and synapses with
accumulation of degenerated mitochondria, dense bodies, and
Hirano-type bodies is the marker of toxic injury of neurons by
fibrillar Abeta. Separation of amyloid cores from neurons and
degradation of amyloid cores by cytoplasmic processes of
hypertrophic astrocytes suggest the protective and defensive
character of astrocytic response to fibrillar Abeta. The growth of
cored plaque from a small plaque with one Microglial
cell with an amyloid star and a few dystrophic neurites to a large
plaque formed by several dozen Microglial
cells seen in old mice is the effect of attraction and activation of
Microglial
cells residing outside of the plaque perimeter. This mechanism of
growth of plaques appears to be characteristic of cored plaques in
transgenic mice. Other features in mouse Microglial
cells that are absent in human brain are clusters of vacuoles,
probably of lysosomal origin. They evolve into circular cisternae
and finally into large vacuoles filled with osmiophilic, amorphous
material and bundles of fibrils that are poorly labeled with
antibody to Abeta. Microglial
cells appear to release large amounts of fibrillar Abeta and
accumulate traces of fibrillar Abeta in a lysosomal pathway
Bechmann I, Nitsch R (2000) Involvement of non-neuronal cells
in entorhinal-hippocampal reorganization following lesions.
Ann.N.Y.Acad.Sci. 911:192-206
Abstract: Entorhinal lesion leads
to anterograde degeneration of perforant path fibers in their main
hippocampal termination zones. Subsequently, remaining fibers sprout
and form new synapses on
the denervated dendrites. This degeneration and reorganization is
accompanied by sequential changes in glial morphology and function.
Within a few hours following the lesion, amoeboid Microglia
migrate into the zone of denervation. Some hours later, signs of
activation can be seen on astrocytes in the zone of denervation,
where both cell types proliferate and remain in an activated state
for more than two weeks. These activated glial cells might be
involved in lesion-induced plasticity in at least two ways: (1) by
releasing cytokines and growth factors which regulate layer-specific
sprouting and (2) by phagocytosis of axonal debris, because myelin
sheaths act as obstacles for sprouting fibers in the central nervous
system. Whereas direct evidence for the former is still missing, the
latter was investigated using phagocytosis-dependent labeling
techniques. Both Microglial
cells and astrocytes incorporate axonal debris. Phagocytosing
Microglial
cells develop the immune phenotype of antigen-presenting cells,
whereas astrocytes strongly express FasL (CD95L), which induces
apoptosis of activated lymphocytes. Thus, the interaction of glial
cells with immune cells might be another, previously underestimated,
aspect of reorganization following entorhinal lesion
Gilbert DL (2000) Fifty years of radical ideas.
Ann.N.Y.Acad.Sci. 899:1-14
Abstract: My role in the free radical
theory of oxygen toxicity is discussed. Rebeca Gerschman and I
published several papers on this subject. This sparked my interest
in geochemistry and I developed the idea that oxygen was the best
qualified biological potential energy source for the following
reasons: great abundance, easily accessible, possession of a high
thermodynamic potential, and its slow reaction rate. Ionization
radiation can be viewed as a catalyst for reactive oxygen species
since a killing dose imparts an infinitesimal small amount of
energy. Next, Carol A. Colton and I showed that in the mammalian
brain that stimulated Microglia
produce the superoxide radical anion and its implications in
Alzheimer's disease is discussed. More recently, I have become
interested in the role of sulfhydryl groups in transcription factors
Gonatas JO, Stieber A, Gonatas NK, Messing A (2000) The golgi
apparatus is present in perisynaptic, subependymal and perivascular
processes of astrocytes and in processes of retinal Muller glia.
Brain Res. 855:23-31
Abstract: The Golgi apparatus (GA) of
innervated rat and chicken skeletal muscle is present in a typical
perinuclear location, and in subsynaptic areas where it disperses
after denervation. It was suggested that the subsynaptic segments of
the GA are linked with functions involved in the maturation and
targeting of synaptic proteins. Similarly, the GA of rat myocardium
is found in a perinuclear location and between myofibrils, adjacent
to the T system of tubules. These findings raise the question
whether the GA of polarized cells is present in a typical
perinuclear location, for the performance of general "housekeeping"
functions, and in distal areas, for the mediation of specialized
functions. Astrocytes may contain GA within their long cytoplasmic
processes which are difficult to identify in thin sections. To
ensure the astrocytic origin of GA in otherwise unidentifiable small
processes, we used transgenic mice expressing the rat MG160 medial
Golgi sialoglycoprotein only in the GA of astrocytes, and visualized
the GA with monoclonal antibody 10A8 (mAb10A8) which reacts only
with rat MG160. Thus, we identified cisternae of the GA in distal
perisynaptic and subependymal processes, in perivascular foot plates
of cerebral astrocytes, and in processes of the Muller glia in the
retina. A similar strategy may be adopted in future investigations
aiming at the detection of elements of the GA in distal processes of
neurons and oligodendrocytes. The functional implications of GA in
perisynaptic astrocytic processes and other processes are unknown.
However, the isolation and molecular characterization of the
perisynaptic subset of astrocytic Golgi may be feasible, since
others have purified the astrocytic glutamate transporter 1 (GLT1)
from crude synaptosomal fractions in which astrocytic processes are
probably unavoidable contaminants
Lopez-Redondo F, Nakajima K, Honda S, Kohsaka S (2000)
Glutamate transporter GLT-1 is highly expressed in activated
Microglia
following facial nerve axotomy. Brain Res.Mol.Brain Res.
76:429-435
Abstract: Glutamate transporters play an important
role in the re-uptake of glutamate after its release from
glutamatergic synapses. So
far five of such transporters subtypes have been cloned from rodent
and human brains. The densities of glutamate transporters are
recognised to be developmentally regulated, but the role of
glutamate transporters in the mechanisms underlying the occurrence
of neuronal traumatic injury has not been widely studied. In the
present study quantitative Western blotting and immunohistochemical
technique were employed to study the expression of GLT-1/EAAT2 in
the facial nuclei of adult rats following unilateral facial nerve
axotomy. The total content of GLT-1 protein decreased in the
ipsilateral axotomised rat facial nucleus. However, activated
Microglia
surrounding motoneurons showed high expression of GLT-1 after facial
nerve axotomy. Parallel studies revealed that primary cultured
Microglial
cells also showed GLT-1-immunoreactivity. To our knowledge, this is
the first direct demonstration of the expression of GLT-1 protein in
activated Microglial
cells, suggesting a neuroprotective role of Microglia
against glutamate excitotoxicity following nerve axotomy
McNamara RK, Lenox RH (2000) Differential regulation of
primary protein kinase C substrate (MARCKS, MLP, GAP-43, RC3) mRNAs
in the hippocampus during kainic acid-induced seizures and synaptic
reorganization. J.Neurosci.Res. 62:416-426
Abstract: In the
mature hippocampus, kainic acid seizures lead to excitotoxic cell
death and synaptic reorganization in which granule cell axons (mossy
fibers) form ectopic synapses
on granule cell dendrites. In the present study, we examined the
expression of four major, developmentally regulated protein kinase C
(PKC) substrates (MARCKS, MLP, GAP-43, RC3), which have different
subcellular and regional localizations in the hippocampus at several
time points (6 hr, 12 hr, 18 hr, 24 hr, 48 hr, 5 days, or 15 days)
following kainic acid seizures using in situ hybridization.
Consistent with previous reports, following kainate seizures, GAP-43
mRNA expression exhibited a delayed and protracted elevation in the
granule cell layer, which peaked at 24 hr, whereas expression in
fields CA1 and CA3 remained relatively unchanged. Conversely, RC3
mRNA expression exhibited a delayed reduction in the granule cell
layer that was maximal at 18 hr, as well as a reduction CA1 at 48
hr, whereas CA3 levels did not change. MARCKS mRNA expression in the
granule cell layer and CA1 remained stable following kainate,
although an elevation was observed in subfield CA3c at 12 hr.
Similarly, MLP mRNA expression did not change in the granule cell
layer or CA1 following kainate but exhibited a protracted elevation
in subfields CA3b,c beginning at 6 hr post-kainate. Collectively
these data demonstrate that different PKC substrate mRNAs exhibit
unique expression profiles and regulation in the different cell
fields of the mature hippocampus following kainic acid seizures and
during subsequent synaptic reorganization. The expression profiles
following kainate seizures bear resemblance to those observed during
postnatal hippocampal development, which may indicate the
recruitment of common regulatory mechanisms
Novikov LN, Novikova LN, Holmberg P, Kellerth J (2000)
Exogenous brain-derived neurotrophic factor regulates the synaptic
composition of axonally lesioned and normal adult rat motoneurons.
Neuroscience 100:171-181
Abstract: Brain-derived neurotrophic
factor has previously been shown to promote survival and axonal
regeneration in injured spinal motoneurons and, also, to modulate
synaptic transmission and regulate the density of synaptic
innervation in a variety of neurons. The present light and electron
microscopic study demonstrates synaptotrophic effects of exogenously
applied brain-derived neurotrophic factor on the synaptic
composition of both normal and axonally lesioned adult rat spinal
motoneurons. After L5-L6 ventral root avulsion, a massive loss of
all types of boutons occurred on the somata of the lesioned
motoneurons which persisted for at least 12 weeks postoperatively.
We found that (i) intrathecal infusion of brain-derived neurotrophic
factor during the first postoperative week did not prevent the
synaptic detachment and activation of glial cells; (ii) prolonged
treatment for four weeks restored synaptic covering and
significantly reduced Microglial
reaction; (iii) the synaptotrophic effect remained significant for
at least eight weeks after cessation of the treatment; (iv)
brain-derived neurotrophic factor mainly supported F-type boutons
with presumably inhibitory function, while it had little effect on
S-type boutons associated with excitatory action; and (v) in normal
unlesioned motoneurons, four weeks of treatment with brain-derived
neurotrophic factor induced sprouting of F-type boutons, a loss of
S-type boutons and motoneuron atrophy.The present data show that
exogenous neurotrophins not only help to restore synaptic circuitry
in axonally injured motoneurons, but also strongly influence the
synaptic composition in normal motoneurons
Terry RD (2000) Cell death or synaptic loss in Alzheimer
disease. J.Neuropathol.Exp.Neurol. 59:1118-1119
Abstract: It is
an erroneous but common assumption that loss of neuronal perikarya
causes the cognitive change in Alzheimer disease. Neither are senile
plaques nor neurofibrillary tangles primarily to blame. In fact, it
is the loss of synaptic contact that leads directly to the personal
devastation. The death of neocortical synapses
in the neuropil between plaques is probably the factor that
activates the Microglia
Wegiel J, Wang KC, Tarnawski M, Lach B (2000) Microglia
cells are the driving force in fibrillar plaque formation, whereas
astrocytes are a leading factor in plague degradation. Acta
Neuropathol.(Berl) 100:356-364
Abstract: Ultrastructural
three-dimensional reconstruction of human classical plaques in
different stages of development shows that Microglial
cells are the major factor driving plaque formation by fibrillar
amyloid-beta (Abeta) deposition. The amount of fibrillar Abeta
released by Microglial
cells and the area of direct contact between amyloid and neuron
determine the extent of dystrophic changes in neuronal processes and
synapses. The volume of
hypertrophic astrocytic processes separating fibrillar amyloid from
neuron is a measure of the protective activation of astrocytes. On
the bases of the volume of amyloid star, Microglial
cells, dystrophic neurites, and hypertrophic astrocytic processes,
and spatial relationships between plaque components, three stages in
classical plaque development have been distinguished: early, mature,
and late. In early plaque, the leading pathology is fibrillar Abeta
deposition by Microglial
cells with amyloid star formation. The mature plaque is
characterized by a balance between amyloid production, neuronal
dystrophy, and astrocyte hypertrophy. In late classical plaque,
Microglial
cells retract and expose neuropil on direct contact with amyloid
star, enhancing both dystrophic changes in neurons and hypertrophic
changes in astrocytes. In late plaques, activation of astrocytes
predominates. They degrade amyloid star and peripheral amyloid
wisps. The effect of these changes is classical plaque degradation
to fibrillar primitive and finally to nonfibrillar, diffuse-like
plaques
Aldskogius H, Liu L, Svensson M (1999) Glial responses to
synaptic damage and plasticity. J.Neurosci.Res. 58:33-41
Abstract:
We review three principally different forms of injury-induced
synaptic alterations. (1) Displacement of presynaptic terminals from
perikarya and dendrites of axotomized neurons, (2) central changes
in primary afferent terminals of peripherally axotomized sensory
ganglion cells, and (3) anterograde Wallerian-type degeneration
following interruption of central axonal pathways. All these
instances rapidly activate astrocytes and Microglia
in the vicinity of the affected synaptic terminals. The evidence
suggests that activated astrocytes play important and direct roles
in synapse elimination and
in the processes mediating collateral reinnervation. The roles of
Microglia
are enigmatic. They undergo activation close to axotomized
motoneuron perikarya, where synapse
displacement occurs, but not adjacent to axotomized intrinsic
central nervous system neurons, where synapse
displacement also occurs. Microglia
are also rapidly activated around central primary sensory terminals
of peripherally axotomized sensory ganglion cells. Occasional
phagocytosis of degenerating axon terminals by Microglia
occur in the latter situation. However, the role of Microglia
may be more oriented toward the general tissue conditions rather
than specifically toward synaptic terminals
Bruce-Keller AJ (1999) Microglial-neuronal
interactions in synaptic damage and recovery. J.Neurosci.Res.
58:191-201
Abstract: An understanding of the role of Microglial
cells in synaptic signaling is still elusive, but the
neuron-Microglia
relationship may have important ramifications for brain plasticity
and injury. This review summarizes current knowledge and theories
concerning Microglial-neuronal
signaling, both in terms of neuron-to-Microglia
signals that cause activation and Microglia-to-neuron
signals that affect neuronal response to injury. Microglial
activation in the brain involves a stereotypical pattern of changes
including proliferation and migration to sites of neuronal activity
or injury, increased or de novo expression of immunomodulators
including cytokines and growth factors, and the full transformation
into brain-resident phagocytes capable of clearing damaged cells and
debris. The factors released from neurons that elicit such
phenotypical and functional alterations are not well known but may
include cytokines, oxidized lipids, and/or neurotransmitters. Once
activated, Microglia
can promote neuronal injury through the release of
low-molecular-weight neurotoxins and support neuronal recovery
through the release of growth factors and the isolation/removal of
damaged neurons and myelin debris. Because Microglia
respond quickly to neuronal damage and have robust effects on
neurons, astrocytes, and oligodendrocytes, Microglial
cells could play potentially key roles in orchestrating the
multicell cascade that follows synaptic plasticity and damage
Hegg CC, Thayer SA (1999) Monocytic cells secrete factors
that evoke excitatory synaptic activity in rat hippocampal cultures.
Eur.J.Pharmacol. 385:231-237
Abstract: Microglia-
and macrophage-induced neuronal death may underlie a number of
neurodegenerative diseases. The effects of factors secreted by
monocytic cells were studied on glutamatergic synaptic transmission
between cultured rat hippocampal neurons. Conditioned media from
differentiated human U937 cells was collected after 24 h and applied
to neurons (0.5%-30% dilution). Unactivated U937 cells spontaneously
released factors that when applied to neuronal cultures evoked
bursts of action potentials and elicited neuronal death (29+/-4%).
Conditioned media collected from U937 cells evoked intracellular
calcium ([Ca(2+)](i)) spiking (0.5%-2% dilution) and at higher
concentrations evoked sustained increases in intracellular calcium
(3%-30% dilution), as measured by indo-1-based photometry in single
neurons. Activation of the U937 cells with zymosin A (500 microg/ml)
enhanced the potency of the conditioned media to increase
intraneuronal [Ca(2+)](i) as indicated by a leftward shift in the
concentration-response curve. Selective antagonists to voltage-gated
Na(+) and Ca(2+) channels and NMDA-gated channels (tetrodotoxin,
nimodipine, and (+/-)-2-amino-5-phosphonopentanoic acid,
respectively) blocked the calcium transients elicited by unactivated
and zymosin -A-treated conditioned media. This pharmacologic profile
is consistent with U937-released factors that excite the synaptic
network that forms between cultured hippocampal neurons
Love S (1999) Oxidative stress in brain ischemia. Brain
Pathol. 9:119-131
Abstract: Brain ischemia initiates a complex
cascade of metabolic events, several of which involve the generation
of nitrogen and oxygen free radicals. These free radicals and
related reactive chemical species mediate much of damage that occurs
after transient brain ischemia, and in the penumbral region of
infarcts caused by permanent ischemia. Nitric oxide, a water- and
lipid-soluble free radical, is generated by the action of nitric
oxide synthases. Ischemia causes a surge in nitric oxide synthase 1
(NOS 1) activity in neurons and, possibly, glia, increased NOS 3
activity in vascular endothelium, and later an increase in NOS 2
activity in a range of cells including infiltrating neutrophils and
macrophages, activated Microglia
and astrocytes. The effects of ischemia on the activity of NOS 1, a
Ca2+-dependent enzyme, are thought to be secondary to reversal of
glutamate reuptake at synapses,
activation of NMDA receptors, and resulting elevation of
intracellular Ca2+. The up-regulation of NOS 2 activity is mediated
by transcriptional inducers. In the context of brain ischemia, the
activity of NOS 1 and NOS 2 is broadly deleterious, and their
inhibition or inactivation is neuroprotective. However, the
production of nitric oxide in blood vessels by NOS 3, which, like
NOS 1, is Ca2+-dependent, causes vasodilatation and improves blood
flow in the penumbral region of brain infarcts. In addition to
causing the synthesis of nitric oxide, brain ischemia leads to the
generation of superoxide, through the action of nitric oxide
synthases, xanthine oxidase, leakage from the mitochondrial electron
transport chain, and other mechanisms. Nitric oxide and superoxide
are themselves highly reactive but can also combine to form a highly
toxic anion, peroxynitrite. The toxicity of the free radicals and
peroxynitrite results from their modification of macromolecules,
especially DNA, and from the resulting induction of apoptotic and
necrotic pathways. The mode of cell death that prevails probably
depends on the severity and precise nature of the ischemic injury.
Recent studies have emphasized the role of peroxynitrite in causing
single-strand breaks in DNA, which activate the DNA repair protein
poly(ADP-ribose) polymerase (PARP). This catalyzes the cleavage and
thereby the consumption of NAD+, the source of energy for many vital
cellular processes. Over-activation of PARP, with resulting
depletion of NAD+, has been shown to make a major contribution to
brain damage after transient focal ischemia in experimental animals.
Neuronal accumulation of poly(ADP-ribose), the end-product of PARP
activity has been demonstrated after brain ischemia in man. Several
therapeutic strategies have been used to try to prevent oxidative
damage and its consequences after brain ischemia in man. Although
some of the drugs used in early studies were ineffective or had
unacceptable side effects, other trials with antioxidant drugs have
proven highly encouraging. The findings in recent animal studies are
likely to lead to a range of further pharmacological strategies to
limit brain injury in stroke patients
Nacher J, Ramirez C, Palop JJ, Molowny A, Luis de la Iglesia
JA, Lopez-Garcia C (1999) Radial glia and cell debris removal during
lesion-regeneration of the lizard medial cortex. Histol.Histopathol.
14:89-101
Abstract: Intraperitoneal injection of the neurotoxin
3-acetylpyridine (3AP) induces a rapid degeneration of the medial
cerebral cortex (lizard fascia dentata) granular layer and of its
zinc enriched axonal projection (lizard mossy fibres). After 6-8
weeks post-lesion the cell debris have been removed and the granular
layer is repopulated by neurons generated in the subjacent ependyma.
Both processes, neuron incorporation and debris removal, seem to be
crucial for successful regeneration. Scavenging processes in the
lesioned mammalian CNS are usually carried out by Microglia
and/or astrocytes. In the lizard cerebral cortex there are no free
astrocytes and the only glial fibrillary acid (GFAP) immunoreactive
cells are radial glia-ependymocytes, similar to those present during
mammalian CNS development. Ependymocytes, in addition to their help
in vertical migrations of just generated immature neurons, built the
cortical glial scaffold, insulate the blood capillaries, form the
outer glial limiting membrane, thus playing an essential role in the
lizard cortical blood-brain barrier. In this study, by means of
GFAP-immunocytochemistry and electron microscopy, we have shown that
radial glial cells participate actively in the removal/phagocytosis
of cellular debris generated in the lesion process: mainly
degenerated synapses, but
interestingly, also some neuronal somata. Cell debris taken up by
ependymocyte lateral processes seem to be progressively transported
to either distal (pial) or proximal (ventricular) poles of the cell,
where they result in lipofuscin accumulations. The hypothetical
subsequent exchange of debris from ependymoglia by
Microglia/macrophages
and Kolmer cells is discussed
Ong WY, Levine JM (1999) A light and electron microscopic
study of NG2 chondroitin sulfate proteoglycan-positive
oligodendrocyte precursor cells in the normal and kainate-lesioned
rat hippocampus. Neuroscience 92:83-95
Abstract: The adult brain
contains a large population of oligodendrocyte precursor cells that
can be identified using antibodies against the NG2 chondroitin
sulfate proteoglycan. The functions of this newly recognized class
of glial cells in the normal or pathological brain are not well
understood. To begin to elucidate these functions, we have examined
the morphology and distribution of oligodendrocyte precursor cells
in the hippocampus and neocortex of normal and kainate-lesioned rats
by anti-NG2 immunocytochemistry using light and electron microscopy.
Large numbers of oligodendrocyte precursor cells were present in all
layers of the neocortex and hippocampus. These cells differed in
their morphology from astrocytes, oligodendrocytes and Microglia.
The processes of these cells often surrounded unlabeled areas of
clear cytoplasm. At the electron microscopic level, some of the
profiles that were enclosed by oligodendrocyte precursor cell
processes contained synaptic vesicles. Other enclosed profiles were
dendrites or dendritic spines. NG2-immunopositive processes were
also observed to interpose between axon terminals containing round
vesicles and dendrites with thick postsynaptic densities. After
kainate injection, the NG2-positive oligodendrocyte precursor cells
in the hippocampus displayed reactive changes characterized by
swollen cell bodies, an increased number of small, filopodial-like
processes, and higher levels of immunodetectable NG2. Both viable
and degenerating oligodendrocyte precursor cells were observed with
electron microscopy. These observations emphasize the dynamic nature
of the oligodendrocyte precursor cell and suggest that, in addition
to participating in the glial reactions to excitotoxic damage,
oligodendrocyte precursor cells may regulate the stability,
structure and function of synapses
in the normal central nervous system
Pasinetti GM, Hassler M, Stone D, Finch CE (1999) Glial gene
expression during aging in rat striatum and in long-term responses
to 6-OHDA lesions. synapse
31:278-284
Abstract: The male rat striatum was examined for
age-related changes in mRNAs expressed in astrocytes and Microglia
in two rat genotypes that differ by 35% in mean and maximum life
spans: F344 and the longer-lived F1 (BN x F344) hybrid. The findings
extend the established age-related increases in GFAP (glial
fibrillary acidic protein) to other glial mRNAs: two lipoprotein
mRNAs that are predominantly expressed in striatal astrocytes, apoE
(apolipoprotein E) and apoJ (apolipoprotein J, clusterin, CLI, or
SGP-2), and two mRNAs expressed in striatal Microglia,
TGF-beta1 and complement C1qB. By Northern blot hybridization, both
genotypes showed progressive increases of GFAP mRNA to > 2.5-fold
by the lifespan. Although the rat strains differed 35% in life span,
the slope of the GFAP mRNA regression on age did not differ.
Relative to GFAP, the increases of apoE, apoJ, C1q, and TGF-beta1
mRNAs were smaller, < or = 1.5-fold. Because prior studies showed
that acute damage to striatal afferents induced astrocyte gene
expression increases resembling those that also occur during aging,
we examined long-term effects of damage to substantia nigra neurons
on striatal astrocyte changes during aging. Young F344 rats were
given 6-OHDA lesions that cause striatal dopamine deficits and
induce GFAP. When examined 15 months later at age 18 months, there
was no effect during prior lesions on the age-related elevation of
GFAP mRNA. We conclude that aging changes in striatal GFAP mRNAs do
not interact with loss of dopaminergic output to the striatum from
6-OHDA lesions and may be independent of the relatively modest
dopaminergic losses during normal aging
Rinaman L, Roesch MR, Card JP (1999) Retrograde transynaptic
pseudorabies virus infection of central autonomic circuits in
neonatal rats. Brain Res.Dev.Brain Res. 114:207-216
Abstract:
Pseudorabies virus (PRV) is widely used to map synaptically-linked
neural circuits in adult animals. The present study sought to
determine whether PRV has similar utility in neonatal rats, and
whether central PRV infection in neonates elicits astrocytic and
Microglia/macrophage
responses similar to those that contribute to specific transynaptic
neuronal infection in adult rats. Retrograde transneuronal infection
of autonomic circuits was examined 24-64 h after injection of an
attenuated strain of PRV (PRV-Bartha) into the ventral stomach wall
of 1-day-old rats. Brain and spinal cord sections were processed for
immunocytochemical detection of PRV. Alternate sections were
processed for immunolocalization of glial fibrillary acidic protein
(GFAP) to identify fibrous astrocytes, or for an antigen associated
with the complement C3bi receptor (OX42) to identify Microglia.
As in adult rats, the number and distribution of infected CNS
neurons in neonatal rats increased progressively with advancing
post-inoculation survival. Infected CNS neurons initially were
restricted to the thoracic intermediolateral cell column and the
dorsal motor nucleus of the vagus. Longer survival times led to
retrograde transynaptic infection of additional neurons in the
thoracic spinal cord, nucleus of the solitary tract, ventrolateral
medulla, and caudal raphe nuclei. At the longest post-inoculation
intervals, infected neurons also were observed in the area postrema
and in certain autonomic-related regions of the rostral brainstem,
hypothalamus, and amygdala. Quantitative analysis of immunolabeling
in the dorsal vagal complex demonstrated that regions containing
neurons at early stages of viral infection displayed increased
astrocytic GFAP immunostaining; conversely, areas containing neurons
at later stages of infection were characterized by a significant
loss of GFAP staining and a parallel increase of OX42
Microglia/macrophage
immunolabeling. We conclude that PRV is effectively transported
through synaptically-linked CNS circuits in neonatal rats, and that
spatiotemporally-ordered responses by non-neuronal cells may
contribute to the synaptic specificity of transneuronal viral
transport
Schiefer J, Kampe K, Dodt HU, Zieglgansberger W, Kreutzberg
GW (1999) Microglial
motility in the rat facial nucleus following peripheral axotomy.
J.Neurocytol. 28:439-453
Abstract: Microglial
motility was studied in living mammalian brain tissue using infrared
gradient contrast microscopy in combination with video contrast
enhancement and time lapse video recording. The infrared gradient
contrast allows the visualization of living cells up to a depth of
60 microm in brain slices, in regions where cell bodies remain
largely uninjured by the tissue preparation and are visible in their
natural environment. In contrast to other techniques, including
confocal microscopy, this procedure does not require any staining or
labeling of cell membranes and thus guarantees the investigation of
tissue which has not been altered, apart from during preparation.
Microglial
cells are activated and increase in number in the facial nucleus
following peripheral axotomy. Thus we established the preparation of
longitudinal rat brainstem slices containing the axotomized facial
nucleus as a source of activated Microglial
cells. During prolonged video time lapse recordings, two different
types of Microglial
cell motility could be observed. Microglial
cells which had accumulated at the surface of the slice remained
stationary but showed activity of the cell soma, developing
pseudopods of different shape and size which undulated and which
were used for phagocytosis of cell debris. Microglial
phagocytosis of bacteria could be documented for the first time in
situ. In contrast, ameboid Microglia
which did not display pseudopods but showed migratory capacity,
could be observed exclusively in the depth of the tissue. Some of
these cells maintained a close contact to neurons and appeared to
move along their dendrites, a finding that may be relevant to the
role of Microglia
in "synaptic stripping", the displacement of synapses
following axotomy. This approach provides a valuable opportunity to
investigate the interactions between activated Microglial
cells and the surrounding cellular and extracellular structures in
the absence of staining or labeling, thus opening a wide field for
the analysis of the cellular mechanisms involved in numerous
pathologies of the CNS
Buttini M, Westland CE, Masliah E, Yafeh AM, Wyss-Coray T,
Mucke L (1998) Novel role of human CD4 molecule identified in
neurodegeneration. Nat.Med. 4:441-446
Abstract: The human CD4
molecule (hCD4) is expressed on T lymphocytes and macrophages and
acts as a key component of the cellular receptor for HIV. At
baseline, hCD4 transgenic mice expressed hCD4 on Microglia,
the resident mononuclear phagocytes of the brain, and showed no
neuronal damage. Activation of brain Microglia
by peripheral immune challenges elicited neurodegeneration in hCD4
mice but not in nontransgenic controls. In post-mortem brain tissues
from AIDS patients with opportunistic infections, but without
typical HIV encephalitis, hCD4 expression correlated with
neurodegeneration. We conclude that hCD4 may function as an
important mediator of indirect neuronal damage in infectious and
immune-mediated diseases of the central nervous system
Cotman CW, Hailer NP, Pfister KK, Soltesz I, Schachner M
(1998) Cell adhesion molecules in neural plasticity and pathology:
similar mechanisms, distinct organizations? Prog.Neurobiol.
55:659-669
Abstract: Brain plasticity and the mechanisms
controlling plasticity are central to learning and memory as well as
the recovery of function after brain injury. While it is clear that
neurotrophic factors are one of the molecular classes that continue
to regulate brain plasticity in the adult central nervous system
(CNS), less appreciated but equally profound is the role of cell
adhesion molecules (CAMs) in plasticity mechanisms such as long term
potentiation, preservation of neurons and regeneration. Ironically,
however, CAMs can also reorganize the extra-cellular space and cause
disturbances that drive the development of brain pathology in
conditions such as Alzheimer's disease and multiple sclerosis.
Candidate molecules include the amyloid precursor protein which
shares many properties of a classical CAM and beta-amyloid which can
masquerade as a pseudo CAM. Beta-Amyloid serves as a nidus for the
formation of senile plaques in Alzheimer's disease and like CAMs
provides an environment for organizing neurotrophic factors and
other CAMs. Inflammatory responses evolve in this environment and
can initiate a vicious cycle of perpetuated neuronal damage that is
medicated by Microglia,
complement and other factors. Certain CAMs may converge on common
signal transduction pathways involving focal adhesion kinases. Thus
a breakdown in the organization of key CAMs and activation of their
signal transduction mechanisms may serve as a new principle for the
generation of brain pathology
Kluge A, Hailer NP, Horvath TL, Bechmann I, Nitsch R (1998)
Tracing of the entorhinal-hippocampal pathway in vitro. Hippocampus
8:57-68
Abstract: In vitro tract tracing allowing for continuous
observation of the perforant path is a crucial prerequisite for
experimental studies on the entorhinal-hippocampal interaction in an
organotypic slice culture containing the entorhinal cortex, the
perforant path, and the dentate gyrus (OEHSC). We prepared
horizontal slices of the temporal entorhinal-hippocampal region of
the rat on a vibratome, and the perforant path axons were traced by
application of the fluorescent tracer Mini Ruby on the entorhinal
cortex. After 2 days in vitro (div), the perforant path became
visible in most cultures. Entorhinal neurons and single perforant
fibers could be followed to the outer molecular layers of the
dentate gyrus by in vitro fluorescence microscopy and it was
possible to monitor the perforant path directly over a period of 25
div. Moreover, ultrastructural analysis proved the existence of
traced perforant path boutons forming synapses
with spines and dendritic shafts in the outer molecular layers of
the dentate gyrus. Transsection of the prelabelled perforant path in
vitro resulted in anterograde degeneration and subsequent
phagocytosis of axonal material by activated Microglial
cells in the zone of denervation. In conclusion, in vitro tracing
demonstrates the maintenance of the entorhinal-hippocampal pathway
in OEHSCs and permits monitoring of dynamic changes in the
prelabeled perforant path after various lesion paradigms, e.g.,
transsection or neurotoxin treatment. This approach permits further
studies on the efficacy of neuroprotectants, cytokines, and growth
factors in the treatment of lesion-induced neuronal degeneration
Nishimura I, Uetsuki T, Dani SU, Ohsawa Y, Saito I, Okamura
H, Uchiyama Y, Yoshikawa K (1998) Degeneration in vivo of rat
hippocampal neurons by wild-type Alzheimer amyloid precursor protein
overexpressed by adenovirus-mediated gene transfer. J.Neurosci.
18:2387-2398
Abstract: In an attempt to elucidate the
pathological implications of intracellular accumulation of the
amyloid precursor protein (APP) in postmitotic neurons in vivo, we
transferred APP695 cDNA into rat hippocampal neurons by using a
replication-defective adenovirus vector. We first improved the
efficiency of adenovirus-mediated gene transfer into neurons in vivo
by using hypertonic mannitol. When a beta-galactosidase-expressing
recombinant adenovirus suspended in 1 M mannitol was injected into a
dorsal hippocampal region, a number of neurons in remote areas were
positively stained, presumably owing to increased retrograde
transport of the virus. When an APP695-expressing adenovirus was
injected into the same site, part of the infected neurons in the
hippocampal formation underwent severe degeneration in a few days,
whereas astrocytes near the injection site showed no apparent
degeneration. These degenerating neurons accumulated different
epitopes of APP, and beta/A4 protein (Abeta)-immunoreactive
materials were undetected in the extracellular space. A small number
of degenerating neurons showed nuclear DNA fragmentation. Electron
microscopic examinations demonstrated that degenerating neurons had
shrunken perikarya along with synaptic abnormalities. Microglial
cells/macrophages were often found in close proximity to
degenerating neurons, and in some cases they phagocytosed these
neurons. These results suggest that intracellular accumulation of
wild-type APP695 causes a specific type of neuronal degeneration in
vivo in the absence of extracellular Abeta deposition
Riehl B, Schlue WR (1998) Morphological organization of
neuropile glial cells in the central nervous system of the medicinal
leech (Hirudo medicinalis). Tissue Cell 30:177-186
Abstract:
Neuropile glial (NPG) cells in the central nervous system of the
medicinal leech, Hirudo medicinalis, were studied by histological,
histochemical and immunocytochemical techniques. The NPG cells are
often surrounded by electron-dense Microglial
cells. The central cytoplasm of NPG cells shows a significant
zonation. The zone around the nucleus contains mitochondria,
glycogen and vesicles. The cytoplasm also contains many ribosomes, a
few dictyosomes and distinct inclusions up to 2 microns in diameter.
A second zone around the perinuclear region is marked by the
occurrence of bundles of intermediate filaments that correspond in
thickness to glial filaments of vertebrates. We found a positive
reaction with polyclonal antibodies against human glial fibrillary
acidic protein (GFAP), and the areas of intense fluorescence
correspond to the regions where intermediate filaments were found to
be abundant. The peripheral zone contains numerous membrane stacks
that could not be contrasted by lanthane nitrate or tannic acid.
Therefore, the membrane stacks could be part of an extensive smooth
endoplasmic reticulum, which is characteristic of cells with active
lipid metabolism
Shafer OT, Chen A, Kumar SM, Muller KJ, Sahley CL (1998)
Injury-induced expression of endothelial nitric oxide synthase by
glial and Microglial
cells in the leech central nervous system within minutes after
injury. Proc.R.Soc.Lond B Biol.Sci. 265:2171-2175
Abstract: It is
known that nitric oxide (NO) is produced by injured tissues of the
mammalian central nervous system (CNS) within days of injury. The
aim of the present experiments was to determine the cellular
synthesis of NO in the CNS immediately after injury, using the CNS
of the leech which is capable of synapse
regeneration, as a step towards understanding the role of NO in
nerve repair. We report that within minutes after crushing the nerve
cord of the leech, the region of damage stained histochemically for
NADPH diaphorase, which is indicative of nitric oxide synthase (NOS)
activity, and was immunoreactive for endothelial NOS (eNOS). On
immunoblots of leech CNS extract, the same antibody detected a band
with a relative molecular mass of 140,000, which is approximately
the size of vertebrate eNOS. Cells expressing eNOS immunoreactivity
as a result of injury were identified after freezing nerve cords, a
procedure that produced less tissue distortion than mechanical
crushing. Immunoreactive cells included connective glia and some
Microglia.
Calmodulin was necessary for the eNOS immunoreactivity: it was
blocked by calmodulin antagonist W7 (25 microM), but not by similar
concentrations of the less potent calmodulin antagonist W12. Thus in
the leech CNS, in which axon and synapse
regeneration is successful, an increase in NOS activity at lesions
appears to be among the earliest responses to injury and may be
important for repair of axons
Vikman K, Robertson B, Grant G, Liljeborg A, Kristensson K
(1998) Interferon-gamma receptors are expressed at synapses
in the rat superficial dorsal horn and lateral spinal nucleus.
J.Neurocytol. 27:749-759
Abstract: Interferon-gamma can
facilitate the spinal nociceptive flexor reflex and may elicit
neuropathic pain-related behavior in rats and mice. Immunoreactivity
for the interferon-gamma receptor (IFN-gamma R) occurs in the
superficial layers of the dorsal horn and the lateral spinal nucleus
in the rat and mouse spinal cord, as well as in subsets of neurons
in the dorsal root ganglia. The aim of the present study was to
examine the cellular localization and origin of the IFN-gamma R in
the spinal cord. As viewed by confocal microscopy, the
immunopositivity for the IFN-gamma R was co-localized with that of
the presynaptic marker synaptophysin and with neuronal nitric oxide
synthase in the lateral spinal nucleus, whereas only a minor overlap
with these molecules was observed in laminae I and II of the dorsal
horn. There was no co-localization of the IFN-gamma R with markers
for astrocytes and Microglial
cells. Ultrastructurally, the IFN-gamma R was found predominantly in
axon terminals in the lateral spinal nucleus, but at postsynaptic
sites in dendrites in laminae I and II. The IFN-gamma R expressed in
neurons in dorsal root ganglia was transported in axons both
centrally and peripherally. Hemisection of the spinal cord caused no
reduction in immunolabelling of the IFN-gamma R in the dorsal horn
or the lateral spinal nucleus. Since rhizotomy does not affect the
immunolabelling in the lateral spinal nucleus, our observation
indicates that the presynaptic receptors in this nucleus are derived
from intrinsic neurons. The localization of the IFN-gamma R in the
spinal cord differed from that of the AMPA glutamate receptor
subunits 2 and 3 and the substance P receptor (NK1). Our results,
showing localization of IFN-gamma R to pre- and postsynaptic sites
in the dorsal horn and lateral spinal nucleus indicate that
IFN-gamma can modulate nociception at the spinal cord level
Wu YP, Ling EA (1998) Transsynaptic changes of neurons and
associated Microglial
reaction in the spinal cord of rats following middle cerebral artery
occlusion. Neurosci.Lett. 256:41-44
Abstract: This study
investigated transsynaptic neuronal damage and Microglial
reaction in the spinal cord contralateral to focal cerebral
ischaemia in rats induced by permanent occlusion of the right middle
cerebral artery (MCA). Three and five days after MCA occlusion, some
neurons in the dorsal horn of lumbar spinal cord underwent
degeneration and they appeared to be engulfed by reactive Microglia;
on the other hand, the ventral horn neurons remained
ultrastructurally intact. It is suggested that the neuronal
degeneration in the dorsal horn was attributed to deafferentation of
the local neurons following ischaemic lesion of the corticospinal
neurons which are the main source of afferent inputs
Appel NM, Rapoport SI, O'Callaghan JP (1997) Sequelae of
parenteral domoic acid administration in rats: comparison of effects
on different anatomical markers in brain. synapse
25:350-358
Abstract: Brain damage following administration of
domoic acid, a structural analog of the excitatory amino acids
glutamic acid and kainic acid, was compared using different anatomic
markers in adult rats. Seven days after administration of domoic
acid (2.25 mg/kg i.p.) or vehicle, brains were collected and
sectioned and stained to visualize Nissl substance using thionin,
argyrophilia using a cupric silver staining method, astroglia using
immunohistochemistry to detect glial fibrillary acidic protein-like
immunoreactivity (GFAP-ir), and activated Microglia
using lectin histochemistry to detect Griffonia simplicifolia I-B4
isolectin (GSI-B4) binding in adjacent sections. In approximately
60% of rats to which it was administered, domoic acid caused
stereotyped behavior within 60 min, followed by convulsions within
2-3 h. Brains of domoic acid-administered rats that did not manifest
stereotyped behavior or convulsions did not differ from brains from
vehicle-administered controls. In animals that had manifested
stereotyped behavior and convulsions, Nissl staining was mostly
unremarkable in brain sections. In contrast, there was intense
argyrophilia in anterior olfactory nucleus, CA1 hippocampus, lateral
septum, parietal (layer IV), piriform, and entorhinal cortices,
ventral posterolateral thalamus, and amygdala. This pattern was
reminiscent of that seen in postmortem specimens from humans who
consumed domoic acid-tainted mussels and in experimental animals
after kainic acid administration. Adjacent sections displayed
astrogliosis, evidenced by increased GFAP-ir, which was more diffuse
than the argyrophilic reaction. Activated Microglia
were revealed using GSI-B4 histochemistry. These data suggest
activation of discrete brain circuits in rats that convulse
following domoic acid administration and subsequent pathological
alterations. The data strongly suggest that neuropathology following
domoic acid occurs only in animals manifesting domoic acid-induced
sterotypy and convulsions. The data do not rule out more insidious
damage in behaviorally normal rats that receive domoic acid
Dal Canto MC (1997) Mechanisms of HIV infection of the
central nervous system and pathogenesis of AIDS-dementia complex.
Neuroimaging Clin.N.Am. 7:231-241
Abstract: In many patients with
AIDS, severe neurologic deficits develop that have been designated
the cf2HIV-associated cognitive-motor complex. cf1 Pathologically,
these symptoms correlate with a low-grade inflammatory condition,
referred to as cf2HIV encephalitis,cf1 in which the most
characteristic change is the presence of multinucleated giant cells.
Cortical changes include neuronal loss and alterations of dendrites
and synapses. There is
pallor of white matter generally associated with the mononuclear
inflammatory infiltrates. The only cells that seem to be directly
infected by HIV are the Microglia/monocyte
and the giant cells derived from fusion of monocytes. It is
hypothesized, therefore, that cortical and white matter alterations
in patients with this syndrome depend on the production of injurious
soluble factors liberated by these cells and by astrocytes under the
influence of many of these same factors. This article reviews recent
advances in the understanding of these secondary effects and
discusses pathogenetic mechanisms of tissue injury
Kotecha SA, Eley DW, Turner RW (1997) Tissue printed cells
from teleost electrosensory and cerebellar structures. J.Comp
Neurol. 386:277-292
Abstract: A modification of the tissue
printing technique was used to acutely isolate and culture cells
from the electrosensory lateral line lobe (ELL), corpus cerebelli
(CCb), and eminentia granularis pars posterior (EGp) of the adult
weakly electric fish, Apteronotus leptorhynchus. Cells were isolated
without the use of proteolytic enzymes and tissue printed as a
monolayer onto glass coverslips through centrifugation in the
presence of a medium designed to preserve cell structure. Tissue
printed cells were reliably distributed in an organotypic fashion
that allowed for the identification of anatomical boundaries between
the ELL and cerebellar regions, distinct sensory maps in the ELL,
and specific cell laminae. Many cells were isolated with an
excellent preservation of soma-dendritic structure, permitting
direct identification of all electrosensory cell classes according
to morphological or immunocytochemical criteria. Several classes of
glial cells were isolated, including small diameter Microglia
and the complex arborizations of oligodendrocytes. A plexus of fine
processes were often isolated in conjunction with cell somata and
dendrites, potentially preserving synaptic contacts in vitro. In
particular, immunolabel for gamma-aminobutyric acid (GABA) revealed
a previously unrecognized network of GABAergic axonal processes in
the CCb and EGp granule cell body and molecular layers. Tissue
printed cells were readily maintained with an organotypic
distribution of glial and neuronal elements for up to 27 days in
culture. This procedure will allow for the isolation of
electrosensory cells from adult central nervous system for
electrophysiological analyses of membrane properties or synaptic
interactions between identified cells
Kretzschmar HA, Giese A, Brown DR, Herms J, Keller B, Schmidt
B, Groschup M (1997) Cell death in prion disease. J.Neural
Transm.Suppl 50:191-210
Abstract: Prion diseases are
neurodegenerative transmissible diseases. The infectious agent,
termed prion, is thought to consist of an altered host-encoded
protein. The pathogenesis of these diseases which typically in a
very short time lead to rampant nerve cell death and astrocytic
gliosis is poorly understood. Investigations using the in situ
endlabeling technique and electron microscopy in a scrapie model in
the mouse (79A strain) show that nerve cell death is due to
apoptosis. A cell culture model using a synthetic peptide of the
prion protein (PrP106-126) shows that this peptide is toxic only to
normal neurons whereas nerve cells derived from PrP knock-out
(PrP0/0) mice are unaffected by this neurotoxic effect. In addition,
Microglia
play a crucial part in this process by secreting reactive oxygen
species. Experiments in animals will have to show whether these cell
culture findings adequately reflect the in vivo pathogenesis
O'Hearn E, Molliver ME (1997) The olivocerebellar projection
mediates ibogaine-induced degeneration of Purkinje cells: a model of
indirect, trans-synaptic excitotoxicity. J.Neurosci.
17:8828-8841
Abstract: Ibogaine, an indole alkaloid that causes
hallucinations, tremor, and ataxia, produces cerebellar
neurotoxicity in rats, manifested by degeneration of Purkinje cells
aligned in narrow parasagittal bands that are coextensive with
activated glial cells. Harmaline, a closely related alkaloid that
excites inferior olivary neurons, causes the same pattern of
Purkinje cell degeneration, providing a clue to the mechanism of
toxicity. We have proposed that ibogaine, like harmaline, excites
neurons in the inferior olive, leading to sustained release of
glutamate at climbing fiber synapses
on Purkinje cells. The objective of this study was to test the
hypothesis that increased climbing fiber activity induced by
ibogaine mediates excitotoxic Purkinje cell degeneration. The
inferior olive was pharmacologically ablated in rats by a neurotoxic
drug regimen using 3-acetylpyridine, and cerebellar damage
attributed to subsequent administration of ibogaine was analyzed
using immunocytochemical markers for neurons and glial cells. The
results show that ibogaine administered after inferior olive
ablation produced little or no Purkinje cell degeneration or glial
activation. That a lesion of the inferior olive almost completely
prevents the neurotoxicity demonstrates that ibogaine is not
directly toxic to Purkinje cells, but that the toxicity is indirect
and dependent on integrity of the olivocerebellar projection. We
postulate that ibogaine-induced activation of inferior olivary
neurons leads to release of glutamate simultaneously at hundreds of
climbing fiber terminals distributed widely over the surface of each
Purkinje cell. The unique circuitry of the olivocerebellar
projection provides this system with maximum synaptic security, a
feature that confers on Purkinje cells a high degree of
vulnerability to excitotoxic injury
Pfrieger FW, Barres BA (1997) Synaptic efficacy enhanced by
glial cells in vitro. Science 277:1684-1687
Abstract: In the
developing nervous system, glial cells guide axons to their target
areas, but it is unknown whether they help neurons to establish
functional synaptic connections. The role of glial cells in synapse
formation and function was studied in cultures of purified neurons
from the rat central nervous system. In glia-free cultures, retinal
ganglion cells formed synapses
with normal ultrastructure but displayed little spontaneous synaptic
activity and high failure rates in evoked synaptic transmission. In
cocultures with neuroglia, the frequency and amplitude of
spontaneous postsynaptic currents were potentiated by 70-fold and
5-fold, respectively, and fewer transmission failures occurred.
Glial cells increased the action potential-independent quantal
release by 12-fold without affecting neuronal survival. Thus,
developing neurons in culture form inefficient synapses
that require glial signals to become fully functional
Schoen SW, Kreutzberg GW (1997) 5'-nucleotidase enzyme
cytochemistry as a tool for revealing activated glial cells and
malleable synapses in CNS
development and regeneration. Brain Res.Brain Res.Protoc.
1:33-43
Abstract: The demonstration of 5'-nucleotidase in neural
tissue is achieved at both the light and electron microscopic levels
by means of an enzyme cytochemical lead method, which is specific,
sensitive and fast. By its activity this adenosine-producing
ecto-enzyme (EC 3.1.3.5) outlines cellular surface membranes at the
ultrastructural level. It is classically known as a marker of myelin
and of astrocytes as well as (activated) Microglial
cells in the mature nervous system. In recent years, we discovered
that 5'-nucleotidase is transiently active within synaptic clefts
under conditions of development and regeneration. The enzyme is also
seen at terminals in the mature retina and olfactory bulb, where
spontaneous synaptic turnover occurs at adulthood. Thus,
5'-nucleotidase cytochemistry is useful in revealing sites of glial
reactions and synaptic plasticity in CNS development and repair. It
is assumed that the molecule affects terminal formation and cell
motility due to dual functions in adenosine production and cell
adhesion. Finally, at the light microscopic level, 5'-nucleotidase
activity displays a dense neuropil staining which identifies
topographic sub-units of certain parts of the nervous system, such
as the striosomes of the basal ganglia, ocular dominance columns of
the visual cortex and parasagittal bands of the cerebellum
Thanos S (1997) Neurobiology of the regenerating retina and
its functional reconnection with the brain by means of peripheral
nerve transplants in adult rats. Surv.Ophthalmol. 42 Suppl
1:S5-26
Abstract: Axotomy-induced degradation of retinal ganglion
cells (RGC) can be delayed if the destructive features of activated
Microglial
cells are pharmacologically neutralized, and prevented if the axons
are permitted to regrow into transplanted autologous peripheral
nerve (PN) pieces. Axotomized central nervous system neurons, whose
regenerating axons are guided to their natural target areas in the
brain with the aid of PN grafts, are capable of establishing
synaptic contacts with normal morphological and electrophysiological
properties. This study was undertaken to 1) morphometrically
characterize and classify the regenerating rat RGC, 2) examine
target-dependent effects on survival of subsets of neurons, and 3)
investigate whether reconnected neurons are capable of restoring
visual functions. In analogy to the normal rat retina, as a first
step, the retrogradely labeled, regenerating RGC were categorized
into five classes which are morphologically distinct and reminiscent
of normal RGC correlates (called types RI, RII, RIII, Rdelta-cells,
and displaced RGC). It appeared that all types of ganglion cells
contributed proportionally to regeneration of axons. Transplantation
of a PN graft which was not reconnected with a central target
(blind-ending group) and monitoring of the extant neurons showed a
progressive disappearance of the regenerating RGC, such that 6
months after surgery predominantly few, large cells survived. When
the retinas were treated with macrophage/Microglia
inhibiting factor (MIF), and the regenerating axons were guided into
the pretectum, predominantly large RGC of type RI survived. Guidance
of the axons into their major natural target, the superior
colliculus (SC), resulted in selective survival of many small,
RII-like RGC. Calculation of the dendritic coverage factors for the
major types of RGC revealed that dendrites of the most abundant,
small cells of type RII overlapped uniformly and covered the retinal
surface completely, whereas cells of types RI and RIII did not
suffice for surface coverage. The results of this first part of the
work suggest that combined suppression of axotomy-induced Microglial
activation and guidance of regenerating axons with a PN graft into
central targets is a suitable technique to produce sufficient
numbers of regenerating axons which may retrieve some functional
properties. Target-specific neuronal contacts are likely involved in
morphological stabilization and better survival of regenerating
neurons. The second goal of this study was to analyze the functional
significance of the reestablished synaptic contacts made by
regenerated retinocollicular neurons. Adult rats were trained in a
T- or Y-maze to obtain a food reward with the aid of visual cues.
One of their optic nerves was transected and the regenerating axons
were guided into the optic tract with a PN graft, to enable them to
reinnervate the SC and thalamus. Postoperative testing of the
animals showed a drastic improvement of visual perception. The
protocol of denervation of the SC (prior to, simultaneous with, or
with a delay with respect to fiber arrival) determined the
performance of the animals. Rats belonging to the first two groups
performed almost as well as they had before the transplantation. The
functional integrity of the retina was assessed by
electroretinography, which revealed typical rod spectral sensitivity
at 380 and 500 nm but reduced responsiveness to illumination. In
accordance, neuroanatomical assessment of the functionally relevant
RGC revealed intact morphologies and multiple synaptic contacts both
within the retina and within the SC. Neuroanatomical tracing of
small contingents of axons throughout the regenerative pathway
revealed a rough retinotopic arrangement within the graft and the
area of termination. Thus, animals could discriminate between
simplified vertical versus horizontal stripes, and visual evoked
potentials were positive after grafting. (ABSTRACT TRUNCATED)
Fine SM, Angel RA, Perry SW, Epstein LG, Rothstein JD,
Dewhurst S, Gelbard HA (1996) Tumor necrosis factor alpha inhibits
glutamate uptake by primary human astrocytes. Implications for
pathogenesis of HIV-1 dementia. J.Biol.Chem.
271:15303-15306
Abstract: Human immunodeficiency virus (HIV)
infection is commonly associated with neurological disease that
occurs in the apparent absence of extensive infection of brain cells
by HIV, suggesting that indirect mechanisms account for
neuropathogenesis in the CNS, perhaps including changes in the
normal neuroprotective functions of astrocytes. To test this
hypothesis, we examined the effect of the pro-inflammatory cytokine,
tumor necrosis factor alpha (TNFalpha), produced by HIV-1-infected
macrophages and Microglia,
on glutamate transport by primary human fetal astrocytes (PHFAs). A
dose-dependent inhibition of high affinity glutamate uptake sites
was observed 12-24 h after addition of exogenous recombinant human
TNFalpha to PHFAs. This effect was specific since it was blocked by
a neutralizing monoclonal antibody directed against TNFalpha.
Furthermore, the inhibitory effect was reproduced by a monoclonal
antibody that is an agonist at the 55-kDa TNF receptor. These
results suggest that the neurotoxic effects of TNFalpha may be due
in part to its ability to inhibit glutamate uptake by astrocytes,
which in turn may result in excitotoxic concentrations of glutamate
in synapses
Hull M, Strauss S, Berger M, Volk B, Bauer J (1996)
Inflammatory mechanisms in Alzheimer's disease. Eur.Arch.Psychiatry
Clin.Neurosci. 246:124-128
Abstract: In recent years many studies
have indicated an involvement of inflammatory mechanisms in
Alzheimer's disease (AD). Acute-phase proteins such as alpha
1-antichymotrypsin and c-reactive protein, elements of the
complement system, and activated Microglial
and astroglial cells are consistently found in brains of AD
patients. Most importantly, also cytokines such as interleukin-6
(IL-6) have been detected in the cortices of AD patients, indicating
a local activation of components of the unspecific inflammatory
system. Up to now it has remained unclear whether inflammatory
mechanisms represent a primary event or only an unspecific reaction
to brain tissue damage. Therefore, we investigated whether IL-6
immunoreactivity could be found in plaques prior to the onset of
neuritic changes, or whether the presence of this cytokine is
restricted to later stages of plaque pathology. We confirmed our
previous observation that IL-6 is detectable in a significant
proportion of plaques in the brains of demented patients. In AD
patients IL-6 was found in diffuse plaques in a significant higher
ratio as would have been expected from a random distribution of IL-6
among all plaque types. This observation suggests that IL-6 may
precede neuritic changes, and that immunological mechanism may be
involved both in the transformation from diffuse to neuritic plaques
in AD and in the development of dementia
Mason A, Muller KJ (1996) Accurate synapse
regeneration despite ablation of the distal axon segment.
Eur.J.Neurosci. 8:11-20
Abstract: In each body ganglion of the
leech Hirudo medicinalis there is a single S-cell. After an S-cell
axon is severed, it regenerates along its surviving distal segment
and reconnects with its synaptic target, the axon of the
neighbouring S-cell. In approximately half the cases the
regenerating axon forms a temporary electrical synapse
specifically with the distal segment, which remains active and
connected to the target, thereby functioning as a splice until
regeneration is complete. To determine whether the distal axon
segment is required for successful regeneration, distal segments of
severed S-cell axons were ablated by intracellular injection of
bacterial protease. Fifty-seven preparations were examined from 2 to
212 days after injection of the axon segment. The extent of S-cell
axon regeneration was assessed electrophysiologically by
intracellular and extracellular recording, and anatomically by
intracellular injection of markers followed by light microscopy and
electron microscopy. The S-cell axons regenerated successfully in
almost 90% of animals examined after 2 weeks or more. In a further
four animals the target S-cell was ablated in addition to the distal
axon segment, permanently disrupting conduction along the S-cell
pathway. Nevertheless, the regenerating axon grew along its usual
pathway and there was no evidence that alternative connections were
formed. It is concluded that, although the distal axon segment can
provide a means for rapid functional repair, the segment is not
required for reliable regeneration of the axon along its usual
pathway and accurate formation of an electrical synapse
Mennerick S, Benz A, Zorumski CF (1996) Components of glial
responses to exogenous and synaptic glutamate in rat hippocampal
microcultures. J.Neurosci. 16:55-64
Abstract: Although glia are
known to be sensitive to exogenously applied neurotransmitter
substances, little is known about how glia respond to neuronal
activity on the millisecond time scale of individual synaptic
events. We have explored the electrophysiological effects of
excitatory neuronal signaling on glial cells in rat hippocampal
microcultures. Exogenous applications of glutamate analogs to
islands of glia revealed a large ionotropic AMPA receptor-mediated
current and a smaller current mediated by electrogenic glutamate
uptake. Glia demonstrated no evidence of NMDA or metabotropic
receptor-mediated currents or membrane conductance changes. Despite
the dominant contribution of AMPA receptors to exogenous glutamate
applications in glia, AMPA receptor currents contributed only
approximately 20% to the response of glia to endogenous glutamate
release from solitary excitatory neurons. Electrogenic glutamate
uptake contributed strongly to glial responses to neuronal
stimulation. In addition, some glia exhibited a residual current is
response to neuronal stimulation that was not attributable to
calcium-dependent transmitter release or to neuronal potassium
efflux. These results help provide a context for understanding the
role of glial transporters and receptors in nervous system signaling
Oster-Granite ML, McPhie DL, Greenan J, Neve RL (1996)
Age-dependent neuronal and synaptic degeneration in mice transgenic
for the C terminus of the amyloid precursor protein. J.Neurosci.
16:6732-6741
Abstract: The molecular basis for the degeneration
of neurons and the deposition of amyloid in plaques and in the
cerebrovasculature in Alzheimer's disease (AD) is incompletely
understood. We have proposed that one molecule common to these
abnormal processes is a fragment of the Alzheimer amyloid precursor
protein (APP) comprising the C-terminal 100 amino acids of this
molecule (APP-C100). We tested this hypothesis by creating
transgenic mice expressing APP-C100 in the brain. We report here
that aging (18-28 month) APP-C100 transgenic mice exhibit profound
degeneration of neurons and synapses
in Ammon's horn and the dentate gyrus of the hippocampal formation.
Of the 106 transgenic mice between 8 and 28 months of age that were
examined, all of those older than 18 months displayed severe
hippocampal degeneration. The numerous degenerating axonal profiles
contained increased numbers of neurofilaments, whorls of membrane,
and accumulations of debris resembling secondary lysosomes near the
cell body. The dendrites of degenerating granule and pyramidal cells
contained disorganized, wavy microtubules. Cerebral blood vessels
had thickened refractile basal laminae, and Microglia
laden with debris lay adjacent to larger venous vessels. Mice
transgenic for Flag-APP-C100 (in which the hydrophilic Flag tag was
fused to the N terminus of APP-C100) showed a similar degree of
neurodegeneration in the hippocampal formation as early as 12 months
of age. The 45 control mice displayed only occasional necrotic cells
and no extensive cell degeneration in the same brain regions. These
findings show that APP-C100 is capable of causing some of the
neuropathological features of AD
Nacimiento W, Sappok T, Brook GA, Toth L, Schoen SW, Noth J,
Kreutzberg GW (1995) Structural changes of anterior horn neurons and
their synaptic input caudal to a low thoracic spinal cord
hemisection in the adult rat: a light and electron microscopic
study. Acta Neuropathol.(Berl) 90:552-564
Abstract: Structural
changes in lumbosacral ventral horn neurons and their synaptic input
were studied at 3, 10, 21, 42, and 90 days following low thoracic
cord hemisection in adult rats by light microscopic examination of
synaptophysin immunoreactivity (SYN-IR) and by electron microscopy.
There was an ipsilateral transient decrease in SYN-IR at the somal
and proximal dendritic surfaces of anterior horn neurons which
extended caudally from the site of injury over a postoperative
(p.o.) period of 42 days. Concomitantly, at 21 days p.o.,
perineuronal SYN-IR started to recover in upper lumbar segments. By
90 days p.o., a normal staining pattern of SYN was noted in upper
and mid lumbar segments, but the perineuronal SYN-IR was still
slightly below normal levels in low lumbar and sacral segments.
Electron microscopy revealed ultrastructural changes coincident with
the alterations in SYN-IR. At 3 days p.o., phagocytosis of
degenerating axon terminals by activated Microglial
cells was observed at the somal and proximal dendritic surfaces of
ventral horn neurons. These changes were most prominent up to two
segments caudal to the lesion. At 10 days p.o., advanced stages of
bouton phagocytosis were still detectable in all lumbosacral motor
nuclei. Additionally, abnormal axon terminals, with a few dispersed
synaptic vesicles and accumulations of large mitochondria, appeared
at the scalloped somal surfaces of anterior horn neurons. At 21 days
p.o., several large lumbosacral motoneurons had developed
chromatolysis-like ultrastructural alterations and motoneuronal cell
bodies had become partially covered by astrocytic lamellae. At 42
days p.o., there was a transient appearance of polyribosomes in some
M-type boutons. In addition, at 42 and 90 days p.o., a few
degenerating motoneurons were detected in all lumbosacral segments,
but most displayed normal neuronal cell bodies contacted by numerous
intact synapses as well as
by astrocytic processes. In contrast to these striking alterations
of synaptic input at somal and proximal dendritic surfaces of
motoneurons, relatively few degenerating boutons were detected in
the neuropil of motor nuclei at all the p.o. times studied. We
suggest that the preferential disturbance of the predominantly
inhibitory axosomatic synapses
on ventral horn neurons may be involved in the mechanisms which
influence the well-established increase in motoneuronal excitability
after spinal cord injury
von Bernhardi R, Muller KJ (1995) Repair of the central
nervous system: lessons from lesions in leeches. J.Neurobiol.
27:353-366
Abstract: In contrast to the limited repair observed
in the mammalian central nervous system (CNS), injured neurons in
the leech reliably regenerate synapses
and restore function with remarkable accuracy at the level of
individual neurons. New and recent results reveal important roles
for Microglial
cells and extracellular matrix components, including laminin, in
repair. Tissue culture experiments have permitted isolation of
neurons and manipulation of their environment, providing insights
into the influence of substrate, electrical activity, and other
cells, including Microglia,
on axon growth and synapse
formation. The results account for distinctive features of
successful repair in the adult leech, where axonal sprouting and
target selection can be influenced by unequal competition between
neurons. Differences between the formation of connections during
embryonic development and repair in the adult include
dissimilarities in the roles of glia and Microglia
in adults and embryos, suggesting that axon growth during
regeneration in the CNS is not simply a recapitulation of processes
observed during embryonic development. It may be possible in the
future to improve mammalian CNS regeneration by recruiting cells
whose counterparts in the leech have been identified as instrumental
in repair
Guntinas-Lichius O, Neiss WF, Gunkel A, Stennert E (1994)
Differences in glial, synaptic and motoneuron responses in the
facial nucleus of the rat brainstem following facial nerve resection
and nerve suture reanastomosis. Eur.Arch.Otorhinolaryngol.
251:410-417
Abstract: Transection and reanastomosis of the facial
nerve with microsurgical sutures in rats (facial-facial anastomosis)
results in the complete regeneration of the facial nucleus, whereas
resection of a 10 mm length of the peripheral facial nerve leads to
degeneration and loss of neurons in the nucleus. Nerve sutures or
resections were performed in 84 female Wistar rats, and the time
course and differences between regenerative and degenerative
reactions in the facial nuclei were compared after survival times of
4-112 days. The volume of the facial nucleus, number of facial
motoneurons and motoneuron density were estimated stereologically by
the physical dissector method. Synaptic plasticity, activation of
astroglia and Microglia
were studied cytochemically with anti-synaptophysin, anti-glial
fibrillary acidic protein and the isolectin Griffonia simplicifolia
I-B4 (GSA I-B4). After facial-facial anastomosis the volume of the
facial nucleus and its number of motoneurons remained constant,
whereas resection of the facial nerve caused shrinkage of the facial
nucleus and loss of one-third of facial motoneurons within 112 days
post-operation. Synaptic stripping, activation of Microglia
and astroglia occurred in the same sequence and were reversible
after both operations, but these reactions were more severe and
prolonged after resection, i.e. without suture of the facial nerve.
It appears to be most important clinically that differences between
de- and regeneration become clear within 7 days post-axotomy. Our
results strongly support reconstruction of the facial nerve as early
as possible after a nerve lesion
Martin LJ, Pardo CA, Cork LC, Price DL (1994) Synaptic
pathology and glial responses to neuronal injury precede the
formation of senile plaques and amyloid deposits in the aging
cerebral cortex. Am.J.Pathol. 145:1358-1381
Abstract: The
cerebral cortices of macaques (ranging in age from 10 to 37 years; n
= 17) were analyzed by immunocytochemistry and electron microscopy
to determine the cellular and subcellular localizations of the
amyloid precursor protein and beta-amyloid protein, the cellular
participants in the formation of senile plaques and parenchymal
deposits of the beta-amyloid protein, and the temporal/spatial
development of these lesions. Amyloid precursor protein was enriched
within the cytoplasm of pyramidal and nonpyramidal neuronal cell
bodies in young and old monkeys. In the neuropil, amyloid precursor
protein was most abundant within dendrites and dendritic spines; few
axons, axonal terminals, and resting astrocytes and Microglia
contained the amyloid precursor protein. At synapses,
amyloid precursor protein was found predominantly within
postsynaptic elements and was enriched at postsynaptic densities of
asymmetrical synapses. The
earliest morphological change related to senile plaque formation was
an age-related abnormality in the cortical neuropil characterized by
the formation of dense bodies within presynaptic terminals and
dendrites and an augmented localization of the amyloid precursor
protein to astrocytes and Microglia.
In most monkeys > 26 years of age, the neocortical parenchyma
exhibited neuritic pathology and plaques characterized by swollen
cytoplasmic processes, interspersed somata of neurons, and reactive
glia within or at the periphery of senile plaques. Neurites and
reactive astrocytes and Microglia
within these plaques were enriched with the amyloid precursor
protein. In diffuse plaques, nonfibrillar beta-amyloid protein
immunoreactivity was visualized within cytoplasmic lysosomes of
neuronal perikarya and dendrites and the cell bodies and processes
of activated astrocytes and Microglia.
In mature plaques, beta-amyloid protein immunoreactivity was
associated with extracellular fibrils within the parenchyma; some
cytoplasmic membranes of degenerating dendrites and somata as well
as processes of activated glia showed diffuse intracellular
beta-amyloid protein immunoreactivity. We conclude that
morphological abnormalities at synapses
(including changes in both pre- and postsynaptic elements) precede
the accumulation of the amyloid precursor protein within neurites
and activated astrocytes and Microglia
as well as the deposition of extracellular fibrillar beta-amyloid
protein; neuronal perikarya/dendrites and reactive glia containing
the amyloid precursor protein are primary sources of the
beta-amyloid protein within senile plaques; and nonfibrillar
beta-amyloid protein exists intracellularly within neurons and
nonneuronal cells prior to the appearance of extracellular deposits
of the beta-amyloid protein and the formation of beta-pleated
fibrils.(ABSTRACT TRUNCATED AT 400 WORDS)
Pallera AM, Schweitzer JB, Book AA, Wiley RG (1994) 192
IgG-saporin causes a major loss of synaptic content in rat olfactory
bulb. Exp.Neurol. 127:265-277
Abstract: An immunotoxin composed
of a monoclonal antibody that recognizes the p75 nerve growth factor
(NGF) receptor disulfide-linked to the ribosome-inactivating protein
saporin selectively eliminates p75-expressing cholinergic neurons in
the basal forebrain, while sparing other neurons in the forebrain,
both cholinergic and noncholinergic. We now report the effect that
intraventricular administration of this immunotoxin has on the
synaptic content of the olfactory bulb, one of the major terminal
fields of the cholinergic basal forebrain system. Control substances
or immunotoxin were given to rats followed by a 2-week survival.
Unilateral transection of the olfactory tract and peduncle was also
studied. Both qualitative and quantitative evaluation of olfactory
bulbs processed for synaptophysin immunohistochemistry indicated
dramatic loss of synapses
in the four regions of neuropil evaluated (glomeruli, outer and
inner halves of the external plexiform layer, and internal plexiform
layer) compared with the administration of control substances.
Surgical transection of the bulb produced a visually similar
decrement, but quantitative studies showed synaptic loss to be
consistently greater following tract transection. The effects of
these two insults on the glial response were remarkably different.
Transection produced an obvious hyperplasia and hypertrophy of both
astrocyte and Microglial
elements, while immunotoxin produced small, almost undetectable
reactions by these two cell types. The results in the glomeruli
strongly suggest an effect of the immunotoxin on either
periglomerular cells or olfactory nerve terminals, whether directly
by NGF receptor (+) structures or by trans-synaptic mechanisms. We
conclude that the immunotoxin produces a specific and large loss of
synapses that does not
produce much glial response
Schoen SW, Kreutzberg GW (1994) Synaptic 5'-nucleotidase
activity reflects lesion-induced sprouting within the adult rat
dentate gyrus. Exp.Neurol. 127:106-118
Abstract: In development,
the ectoenzyme 5'-nucleotidase marks maturing cerebellar and
cortical synapses, but it
is localized in glial cells in the normal, adult nervous system.
With a histochemical lead technique, we have now investigated its
localization during reactive synaptogenesis in the dentate gyrus of
adult rats deprived of entorhinal afferents. A band of enhanced
5'-nucleotidase reaction product was present in the outer portions
of the dentate molecular layer between 5 and 75 days after
destruction of the ipsilateral entorhinal cortex. At the
ultrastructural level, 5'-nucleotidase-positive Microglia
and degenerating axon terminals were numerous within this band
during the first postoperative week. Between Days 7 and 75, intact
synapses were found that
exhibited 5'-nucleotidase reaction product in their clefts.
Astrocytic labeling was abundant. No enzyme-positive synapses
and few labeled glial elements were present in the control molecular
layer. Conspicuous 5'-nucleotidase activity within synaptic clefts
of mossy fiber terminals was present between Postoperative Days 10
and 40 on the operated side, but the staining was sporadic on the
control side. We conclude that 5'-nucleotidase is associated with
lesion-induced synaptic remodeling in the dentate gyrus. The band of
5'-nucleotidase reaction product within the outer molecular layer
corresponds to the zone where the lesioned entorhinal fibers
degenerate and where other afferents sprout. Here, the transient
appearance of 5'-nucleotidase within synaptic clefts parallels the
time course of synaptic reinnervation. The enzyme is also indicative
of the sprouting response of mossy fiber terminals. Functional
properties of 5'-nucleotidase in purinergic neuromodulation and
cellular adhesion may be relevant for the generation and plasticity
of synaptic contacts
Beyreuther K, Pollwein P, Multhaup G, Monning U, Konig G,
Dyrks T, Schubert W, Masters CL (1993) Regulation and expression of
the Alzheimer's beta/A4 amyloid protein precursor in health,
disease, and Down's syndrome. Ann.N.Y.Acad.Sci. 695:91-102
Abstract:
A four- to fivefold overexpression of the gene for the Alzheimer
beta/A4 amyloid precursor protein (APP) in individuals with Down's
Syndrome (DS) appears to be responsible for the fifty year earlier
onset of Alzheimer's disease (AD) pathology in DS compared to the
normal population. It is therefore likely that a deregulated
overexpression of the APP gene is a risk factor for the beta/A4
amyloid formation. To test this hypothesis and to get a better
understanding of how APP expression is regulated, we studied the 5'
control region of the human APP gene, alternative splicing of the 19
APP exons, and APP biogenesis, metabolism and function. The analysis
of the APP promoter revealed its similarity with those of
housekeeping genes by the presence of a GC-rich region around the
transcription start site and the lack of a TATA box. Gene transfer
experiments showed this GC-rich region to contain overlapping
binding sites for different transcription factors whose binding is
mutually excluded. An imbalance between these factors may cause APP
overexpression and predispose to AD pathology. Another putative risk
factor for AD is regulation of splicing of exon 7 in APP mRNA's
which changes in brain during aging. This is relevant for APP
processing since exon 7 codes for a Kunitz protease inhibitory
domain. Investigation of further splicing adjacent to the beta/A4
exons 16 and 17 which might also interfere with APP processing led
to the identification of the leukocyte-derived (L-APP) splice forms
which lack exon 15. In brain this splicing occurs in activated
astrocytes and Microglia.
The localization of APP at synaptic sites in brain suggests that APP
regulation and expression are critical determinants of a potential
and early impairment of central synapses.
This may be the case during pathological evolution of AD and DS when
beta/A4 derived from synaptic APP is converted to beta/A4 amyloid by
radical generation
Bruckner G, Brauer K, Hartig W, Wolff JR, Rickmann MJ,
Derouiche A, Delpech B, Girard N, Oertel WH, Reichenbach A (1993)
Perineuronal nets provide a polyanionic, glia-associated form of
microenvironment around certain neurons in many parts of the rat
brain. Glia 8:183-200
Abstract: The nature and function of
previously described perineuronal nets are still obscure. In the
present study their polyanionic components were demonstrated in the
rat brain using colloidal iron hydroxide (CIH) staining. In
subcortical regions, such as the red nucleus, cerebellar, and
vestibular nuclei, most neurons were ensheathed by CIH-binding
material. In the cerebral cortex perineuronal nets were seen around
numerous nonpyramidal neurons. Biotinylated hyaluronectin revealed
that hyaluronan occurs in perineuronal nets. Two plant lectins
[Wisteria floribunda agglutinin (WFA) and Vicia villosa agglutinin
(VVA)] with affinity for N-acetylgalactosamine visualized
perineuronal nets similar to those rich in anionic components.
Glutamic acid decarboxylase (GAD)-immunoreactive synaptic boutons
were shown to occupy numerous meshes of perineuronal VVA-positive
nets. Electron microscopically, VVA binding sites were scattered
throughout perisynaptic profiles, but accumulated at membranes and
in the extracellular space except not in synaptic clefts. To
investigate the spatial relationship between glial cell processes
and perineuronal nets, two astrocytic markers (S100-protein and
glutamine synthetase) were visualized at the light and electron
microscopic level. Two methods to detect Microglia
by the use of Griffonia simplicifolia agglutinin (GSA I-B4) and the
monoclonal antibody, OX-42, were also applied. Labelled structures
forming perineuronal nets were observed with both astrocytic, but
not with Microglial,
markers. It is concluded that perineuronal nets are composed of a
specialized type of glia-associated extracellular matrix rich in
polyanionic groups and N-acetylgalactosamine. The net-like
appearance is due to perisynaptic arrangement of the astrocytic
processes and these extracellular components. Similar to the
ensheathment of nodes of Ranvier, perineuronal nets may provide a
special ion buffering capacity required around various, perhaps
highly active, types of neurons
Fix AS, Horn JW, Wightman KA, Johnson CA, Long GG, Storts RW,
Farber N, Wozniak DF, Olney JW (1993) Neuronal vacuolization and
necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA)
antagonist MK(+)801 (dizocilpine maleate): a light and electron
microscopic evaluation of the rat retrosplenial cortex. Exp.Neurol.
123:204-215
Abstract: MK(+)801 (dizocilpine maleate) is a
noncompetitive antagonist at the N-methyl-D-aspartate (NMDA)
receptor, the major glutamate receptor at excitatory synapses
in the central nervous system. Since NMDA antagonists are
neuroprotective, there is interest in their development for
treatment of cerebral ischemia. Unfortunately, many of these
compounds also induce vacuole formation in neurons of the rat
retrosplenial cortex (Olney et al., Science 244: 1360-1362, 1989).
Although vacuolization was initially reported to be reversible with
MK(+)801, preliminary data later suggested that higher doses might
produce neuronal necrosis. To explore this issue, young male
Sprague-Dawley rats were given a single subcutaneous dose of vehicle
or 1, 5, or 10 mg/kg MK(+)801. At 4 h and 1, 2, 3, 4, 7, and 14 days
postdose (DPD), the retrosplenial cortex was examined by light and
electron microscopy. At 4 h, vacuoles occurred in neurons of
retrosplenial cortical layers 3 and 4 in all rats given MK(+)801.
Mitochondria and endoplasmic reticulum contributed to vacuole
formation. At 1 DPD, vacuoles or necrotic neurons were rarely
observed. At all subsequent time points, necrotic neurons were
readily evident in rats given 5 or 10 mg/kg MK(+)801, but only
rarely evident in rats given 1 mg/kg. Necrotic neurons were
associated with reactive Microglial
cells that contained electron-dense debris ultrastructurally. If
similar dose-dependent neuronal necrosis proves to be a feature of
other NMDA antagonists, such effects might raise concerns for the
development and use of these compounds in human cerebrovascular
diseases
Gehrmann J, Gold R, Linington C, Lannes-Vieira J, Wekerle H,
Kreutzberg GW (1993) Microglial
involvement in experimental autoimmune inflammation of the central
and peripheral nervous system. Glia 7:50-59
Abstract: Microglial
cells form a network of potential antigen presenting cells
throughout the nervous system. Much progress has recently been made
towards a better understanding of their immunological properties.
This study examines their activation in 2 models of T cell-mediated
autoimmune inflammation of the nervous system, experimental
autoimmune encephalomyelitis (EAE) and its peripheral counterpart,
experimental autoimmune neuritis (EAN), induced by the transfer of
antigen-specific T cell lines. In both models Microglial
activation occurs at early stages of the disease. Activated
Microglial
cells show an increased expression of MHC class I and II antigens.
In EAE ultrastructural analysis revealed that MHC antigen expression
is pronounced on perivascular Microglial
cells, suggesting this cell population may be important for antigen
presentation at a site close to the blood-brain barrier. In contrast
to EAE, the Microglial
reaction in EAN occurs at sites remote from the inflammatory
response in the peripheral nerve, not only in the spinal cord but
also in the terminal projection fields of primary sensory neurons in
the lower brainstem. This early Microglial
activation in EAN suggests that a rapid and remote signaling
mechanism can operate following peripheral inflammation.
Immuno-electron microscopy revealed that activated Microglial
cells are also involved in the synaptic deafferentation of spinal
cord motoneurons during autoimmune reactions. The rapid involvement
of Microglial
cells in experimental autoimmune inflammation of the nervous system
further points to their role as the main intrinsic immuneffector
cell population of the central nervous system
Graeber MB, Bise K, Mehraein P (1993) Synaptic stripping in
the human facial nucleus. Acta Neuropathol.(Berl)
86:179-181
Abstract: An autopsy case of severe peripheral facial
nerve paresis with disconnection of synapses
from facial motor neurons is reported. A 77-year-old man presented
with left-sided otitis media and subsequent development of facial
nerve paresis. Three months later, the patient died of an acute
gastrointestinal bleeding from a chronic duodenal ulcer. Gross
inspection of the brain revealed non-stenosing arteriosclerotic
vascular changes and a single small cystic lesion in the right
putamen. Microscopically, marked chromatolytic changes were observed
in the left facial nucleus. Immunocytochemistry for synaptophysin
revealed a marked loss of afferent synaptic contacts from somatic
and stem dendritic surface membranes of all chromatolytic motor
neurons. Wrapping of a number of neurons by newly formed glial
fibrillary acidic protein-positive astrocytic cell processes could
be detected in the regenerating facial motor nucleus. In addition,
expression of HLA-DR was increased on a small number of Microglia
and perivascular cells. These changes were absent from the
contralateral, normal-appearing facial nucleus. To our knowledge,
this case provides the first evidence for disconnection of synapses
following peripheral nerve lesioning in humans. Occurrence of
synaptic stripping is likely to explain nuclear hyperexcitability
and failure of recovery of complex fine motor movements that are
commonly observed following peripheral injury to the facial nerve
Mudrick-Donnon LA, Williams PJ, Pittman QJ, MacVicar BA
(1993) Postsynaptic potentials mediated by GABA and dopamine evoked
in stellate glial cells of the pituitary pars intermedia.
J.Neurosci. 13:4660-4668
Abstract: Studies have shown that many
glial cells in the CNS possess receptors for neurotransmitters and
that synapse-like contacts
exist between glial cells and axonal terminals. Although
synapse-like contacts are
present between the glial cells (stellate cells) of the pituitary
pars intermedia and the axons from the arcuate nucleus, it is not
known whether these cells are under synaptic control. The objective
of the present study was to determine whether transmitter-mediated
postsynaptic potentials occurred in the stellate cells of the rat
pituitary pars intermedia. Whole pituitaries were maintained in
vitro, and a stimulating electrode was placed on the stalk to
activate afferent fibers. Intracellular recordings were obtained
with sharp microelectrodes. Stellate cells showed
electrophysiological characteristics of macroglia including a
resting potential more negative than -65 mV, low input resistance (<
50 M omega), and no detectable voltage-activated conductances.
Single-pulse afferent nerve (stalk) stimulation evoked a
[Ca2+]o-dependent postsynaptic response in the stellate cells
consisting of a depolarization (< 500 msec) and a long-lasting
hyperpolarization (45-75 sec). The depolarization was mimicked by
GABA application and blocked by the GABAA antagonist bicuculline
(100 microM). Repetitive stimulation of the stalk increased the
amplitude and prolonged the GABA-mediated depolarization, during
which a decrease in input resistance was observed. The
hyperpolarization was mimicked by dopamine and blocked by the D2
antagonists sulpiride (2 microM) and domperidone (10 microM).
Nipecotic acid (100 microM; an inhibitor of GABA uptake) or GBR
12909 (15 microM; an inhibitor of dopamine uptake) had minimal
effects on the synaptic responses.(ABSTRACT TRUNCATED AT 250 WORDS)
Svensson M, Aldskogius H (1993) Synaptic density of
axotomized hypoglossal motorneurons following pharmacological
blockade of the Microglial
cell proliferation. Exp.Neurol. 120:123-131
Abstract: The purpose
of the present study was to examine the possible role of reactive
Microglia
in the removal of presynaptic terminals following motor axon injury.
Quantitative electron microscopy was used to examine synaptic
numbers and total relative synaptic coverage on hypoglossal neuronal
perikarya following hypoglossal nerve transection in the rat with or
without pharmacological blockade of the axotomy-induced Microglial
cell proliferation. In a previous study we have shown that the
axotomy-induced Microglial
cell proliferation is selectively inhibited by continuous infusion
of cytosine-arabinoside (ARA-C) into the ventricular system of the
adult rat brain. Adopting this procedure in the present study
resulted in an almost complete elimination of reactive Microglia.
There was a statistically significant decrease in the number of
synapses and the relative
synaptic coverage in untreated as well as ARA-C-treated animals 4
and 7 days after nerve transection. Immunocytochemical labeling of
terminals in the hypoglossal nucleus using antibodies to
synaptophysin showed a reduction in immunoreactivity around
hypoglossal nerve cell bodies ipsilateral to nerve transection in
both groups of animals. These results indicate that reactive
Microglia
are not responsible for detachment of presynaptic terminals
following motor axon injury
Neiss WF, Lichius OG, Angelov DN, Gunkel A, Stennert E (1992)
The hypoglossal-facial anastomosis as model of neuronal plasticity
in the rat. Anat.Anz. 174:419-433
Abstract: Hypoglossal-facial
cross anastomosis (HFA) causes regeneration with change of function,
as the axotomized hypoglossal motoneurons sprout into the facial
plexus and reinnervate the mimic musculature. Following HFA,
hypoglossal-hypoglossal single anastomosis (HHA) and resection of
8-10 mm peripheral hypoglossal nerve in 190 female adult Wistar
rats, we compared the axon reactions in the hypoglossal nucleus
during 1) regeneration with change of function, 2) regeneration with
restoration of original function and 3) degeneration of the nucleus.
Following postoperative survival times of 1-16 weeks we estimated
the volume of the hypoglossal nucleus and counted the number of
hypoglossal neurons with the physical disector on both sides of the
brainstem. Additional sections of the same animals were reacted with
anti-synaptophysin, anti-GFAP and the isolectin Griffonia
simplicifolia I-B4 (GSA I-B4) as cytochemical markers for
presynaptic boutons, activated astroglia and Microglia.
After HHA and HFA all hypoglossal neurons survive and the volume of
the hypoglossal nucleus remains constant. Resection of the
hypoglossal nerve leads to the loss of one third of the hypoglossal
neurons and of one third of the volume of the hypoglossal nucleus
within 16 weeks post operation. Hypoglossal-facial anastomosis and
hypoglossal-hypoglossal anastomosis differ in postoperative swelling
of the hypoglossal nucleus, Microglia
and astroglia activation and the duration of synaptic stripping. All
differences are limited to the acute growth phase during
regeneration. It is concluded that hypoglossal-facial anastomosis
provides more stimulation and facilitates faster recovery of the
hypoglossal nucleus than does hypoglossal-hypoglossal anastomosis
Tay SS, Wong WC (1992) Long-term effects of alloxan-induced
diabetes on the nucleus ventralis posterolateralis in the thalamus
of the rat. Acta Anat.(Basel) 144:51-58
Abstract: The present
paper describes the long-term ultrastructural changes in the nucleus
ventralis posterolateralis of the thalamus of male Wistar rats after
alloxan-induced diabetes. Degenerating dendrites were characterized
by an electron-dense cytoplasm with scattered endoplasmic reticulum
and ribosomes. Degenerating axon terminals were characterized by an
electron-dense cytoplasm and clustering of small spherical agranular
vesicles. Degenerating axon terminals formed axosomatic synapses
with seemingly normal cell bodies and axodendritic synapses
with normal as well as degenerating dendrites. Degenerating axons
(both myelinated and unmyelinated) were readily encountered in the
neuropil. Activated Microglial
and astrocytic cells in the neuropil were in the process of
phagocytosis or had residua in their cytoplasm
Becker L, Mito T, Takashima S, Onodera K (1991) Growth and
development of the brain in Down syndrome. Prog.Clin.Biol.Res.
373:133-152
Abstract: The brain of a child with Down syndrome
develops differently from a normal one, attaining a form reduced in
size and altered in configuration. Directly related to the mental
retardation are neuronal modifications manifest as alterations of
cortical lamination, reduced dendritic ramifications, and diminished
synaptic formation. However, selected cholinergic marker enzymes
such as choline acetyl transferase and acetyl cholinesterase have
shown no alterations in young children with Down syndrome. The pace
of the neuronal transformations is related to stage of maturation.
With early growth and development, the normal dendritic tree
continuously expands. In Down syndrome, at 4 months of age, the
neurons show a relatively expanded dendritic tree, but during the
first year the dendrites stop growing and become atrophic relative
to control neurons. Accompanying these neuronal irregularities are
subtle alterations of other cell types: astrocyte,
oligodendrogliocyte, Microglia,
and endothelial cell. In early infancy, one of the astrocytic
markers, GFAP, is not altered, but there is greater expression of
S-100 protein in the temporal lobe in Down syndrome.
Oligodendrogliocyte dysfunction is reflected in delayed myelination
in pathways of frontal and temporal lobes. Microglia
appear more prominent in Down syndrome. A minority of children with
Down syndrome have vascular dysplasias and focal calcification of
basal ganglia. In young children, expression of beta-amyloid in Down
syndrome is no different than in normal children but disappears
after age two, only to reappear in adults. As some of these studies
suggest, the identification of genes on chromosome 21 and the
determination of the gene product allow the production of specific
antibodies and, through immunohistochemical techniques, the
identification of the expression of these proteins in both normal
development and Down syndrome. Specifically, the localization and
appearance in development of proteins such as the beta-subunit of
S-100, beta-amyloid (A4 protein), superoxide dismutase, and OK-2 are
providing the means for better understanding the morphogenesis of
the cellular and eventually molecular basis for the mental
retardation in Down syndrome
Kristt DA (1987) Morphological responses to local CNS trauma:
sprouting and synaptogenesis within membranes implanted into mature
cerebral cortex of the rat. J.Neuropathol.Exp.Neurol.
46:668-681
Abstract: The purpose of this study was to document in
vivo neuronal sprouting in response to local trauma of the mature
cerebral neocortex. The experimental approach enabled direct and
unequivocal ultrastructural identification of newly sprouted
neuronal processes and their synaptic relationships. Morphologically
detectable factors that influence neuronal sprouting were also
assessed. Tiny fragments of porous, synthetic membrane were
implanted into the mature neocortex of the rat. After one week,
axons, dendrites, growth cone-like structures, synapses,
and processes from astrocytes and Microglia
were present deep within the interstices of the implant.
Morphometric analysis of synapses
within the implant, support the qualitative impression of active
neuronal ingrowth and de novo synaptogenesis by these sprouted
elements. Astrocytic processes appear to comprise the major barrier
to neuronal invasion of the implant. Several observations suggested
that glia sometimes may facilitate neuronal ingrowth. These findings
provide direct morphological documentation of axonal and dendritic
plasticity in the mature rat neocortex. The work demonstrates a
strategy that could be useful for further evaluating the cellular
mechanism of in vivo neuronal regeneration
Scott T, Pesce C (1987) The ultrastructure of the nervous
tissue in a benign teratoma. Acta Neuropathol.(Berl)
73:281-286
Abstract: The ultrastructure of the nervous tissue in
a benign ovarian teratoma is described. This tissue was organized
into areas having both "meningeal" and "ependymal"
surfaces, between which were found astrocytes, ependymal cells,
neurones with synapses and
Microglia.
These cells all had ultrastructural similarities to their normal
counterparts in the nervous system. In addition, some signs of
degenerative change--due possibly to the abnormal location of the
nervous tissue--were observed. Oligodendrocytes and myelin were
absent, possibly because of vascular insufficiency
Ling EA, Wong WC, Yick TY, Leong SK (1986) Ultrastructural
changes in the dorsal motor nucleus of monkey following bilateral
cervical vagotomy. J.Neurocytol. 15:1-15
Abstract: The neurons of
the dorsal motor nucleus (DMN) of the monkey (Macaca fascicularis)
were of two main types: small (13 X 8 micron) and medium-sized (20 X
13 micron). The latter, which were the predominant form, contained a
pale oval nucleus surrounded by organelle-rich cytoplasm. Between
one and three long principal dendrites per section profile arose
from each of the somata. Both axosomatic and axodendritic synapses
were seen on these cells although the latter were more common. No
structural changes were noted in the DMN 1-3 days after bilateral
cervical vagotomy. Some of the dendrites of the medium-sized
axotomized vagal neurons appeared darkened 5-10 days after the
operation. With longer surviving intervals, i.e. 21 and 28 days
after operation, darkened dendrites were more commonly seen and the
cytoplasmic density of these dendrites was dramatically enhanced.
Their mitochondria were pale and some of them also showed
vesiculation. Both normal and degenerating axon terminals were seen
to form synaptic contacts with the darkened dendrites. The
degenerating axon terminals were characterized by the clumping of
their round agranular vesicles. Both darkened dendrites and
degenerating axon terminals were phagocytosed by hypertrophied
astrocytes and activated Microglial
cells. Blood elements infiltrating into the DMN were a possible
source for some of the neural macrophages. It was concluded from the
present study that the dendrites of the vagal neurons were the first
structures to degenerate in axotomy and these were subsequently
removed by glial elements. Degenerating axon terminals on the
darkened dendrites could represent endings of the central processes
of peripheral vagal ganglion cells that had undergone
transganglionic degeneration after damage to their peripheral
processes
Karcsu S, Toth L, Laszlo FA (1985) [Ultrastructural changes
in the supraoptica-neurohypophyseal system after induction of
lesions in the pituitary stalk in rats]. Acta Histochem.
76:183-192
Abstract: Fine structural changes occurring in the
supraoptic nucleus and the neural lobe have been studied in rats
following the electrolytic lesion of the hypophysial stalk.
Supraoptic neurosecretory neurones undergo a typical chromatolytic
reaction. In addition, proliferating Microglial
cells disconnect axosomatic synapses
and phagocytose degenerating neurones. Surviving neurones show signs
of structural restitution 3 to 4 weeks after surgery. In the
neurohypophysis degeneration of secretory nerve endings started with
the disintegration of secretory vesicles 3 to 4 d postoperatively.
Degenerated axon terminals were engulfed by pituicytes. Signs
indicative of axonal regeneration were not observed in the neural
lobe up to the end of the 4th postoperative week
Leibnitz L, Kastner I, Bar B (1985) [Morphologic and
histochemical changes in the secondary focus following
cobalt-induced epileptogenic bioelectrical activity of the visual
cortex in the adult rat]. J.Hirnforsch. 26:601-614
Abstract:
Implantation of cobalt-agar rods into the visual cortex of 16 adult
rats induced in some of the animals epileptiform bioelectrical
activity and provoked in all of them histological and histochemical
changes in the region of the implantation (primary focus) as well as
in some ipsilateral projection sites of the visual cortex (secondary
foci). The changes within the secondary foci are demonstrated in the
Corpus geniculatum laterale, pars dorsale (dLGN), by means of 18
histochemical and 5 histological methods. Together with the
appearance of hyperactive and degenerating neurones combined with
neuronophagy and diminution of the number of synapses
a marked gliosis developed, especially an increase of Microglia.
The destruction of the tissue induced a depression of energy and
transmitter metabolism and intensified lytic processes. This is
confirmed by the decreased activities of LDH, SDH, GPDH, G6PDH,
NAD(P)H-TR, GABA-T and GDH and the increased activity of acid
phosphatase in the neuropil of the secondary foci. Single
hyperactive nerve and glial cells were accented by high activities
of those enzymes which had a reduced activity in the neuropil. Since
in our experiments agar-rods without cobalt never induced
histological or histochemical changes in subcortical grisea of the
visual system, the secondary foci seem to result from the direct
influence of the cobalt, migrating in the corticothalamic projection
pathway and identifiable in the dLGN by the TIMM technique
Dellmann HD, Stahl SJ (1984) Fine structural cytology of the
rat subfornical organ during ontogenesis. Brain Res.Bull.
13:135-145
Abstract: The main developmental events in the
subfornical organ take place between 17 fetal days (fd) and 5 days
post natum (dpn) at which time it possesses most of its mature fine
structural characteristics. The surface regional characteristics of
ependymal cells differentiate primarily during this time as well,
while the ependymal cellular fine structure, shape and relationship
with neurons and the vascularity are well established prior to
birth. Undifferentiated neurons contain glycogen prior to 19 fd and
then differentiate by developing processes and organelles
characteristic of neurons. By 5 dpn, the various types of neurons
found in the mature subfornical organ are all present, except for
giant vacuolated cells. synapses
containing only electron-lucent vesicles are first present at 20 fd,
those containing additional electron-dense vesicles at 3 dpn.
Microglial
cells are first identifiable at 17 fd, and the first protoplasmic
astrocytes are recognizable at 21 fd, while fibrous astrocytes are
not detectable prior to 7 dpn. By 5 dpn, the cytological elements of
the subfornical organ are all in place, and further developmental
changes leading to adult fine structural characteristics by 30 dpn
are essentially quantitative in nature
Garcia Verdugo JM, Berbel NP, Regidor GJ, Lopez GC (1984)
Ultrastructure of neuronal cell bodies in the medial cortex of
Lacerta galloti. J.Hirnforsch. 25:187-196
Abstract: According to
ultrastructure, size, and location within the medial cortex of
Lacerta galloti, seven basic kinds of neuronal somata are described
in this study. In the outer plexiform layer of the medial cortex
only a few somata can be detected. There, moreover some
oligodendroglia and Microglia
cells a few neuronal somata showing conspicuous nuclear
invaginations and spongious chromatin (A) can be seen. The granular
layer of the medial cortex is formed by up to seven strata of
tightly packed neuronal somata in a pattern which resembles that of
the profound stratum of the fascia dentata of the mammalian
hippocampus. In this layer four neuronal somata can be seen: somata
with nuclear invaginations, generally located aside the outer
plexiform layer (in the upper stratum) (B); very abundant little
neuronal somata with chromatin clumps (C); vertically fusiform
shaped neuronal somata with numerous polyribosomes (D); and big
neuronal somata with spongious chromatin (E). In the inner plexiform
layer, there are a variety of scarce neuronal somata intermingled
with ependymal sprouts and fiber tracts running from other cortical
areas; two main types are described: big horizontal somata which are
almost covered by axonic endings making synapses
(F) and somata with dense cytoplasmic matrix and some small nuclear
invaginations (G). Location of soma, frequency, and biometric data
of them have been used to make a comparison with neuronal types of
the medial cortex of Lacerta galloti defined by Golgi impregnations
Sterman AB, Sposito N (1984) Motoneuron axosomatic synapses
are altered in axonopathy. J.Neuropathol.Exp.Neurol.
43:201-209
Abstract: This study was designed to answer two
questions: 1) are synapses
on motoneuron cell bodies affected during toxic neuropathy and 2)
what is the nature and extent of the changes? We describe synaptic
alterations on motoneuron cell bodies during intoxication with
2,5-hexanedione, a prototype neurotoxin known to induce axonal
degeneration. Ultrastructural study of lumbar motoneurons from
experimental and control rats revealed an array of pathologic
changes including: partial and, less frequently, complete detachment
of synaptic boutons; synaptic degeneration in a minority of boutons;
and involvement of both Microglia
and astrocytes. Quantitatively, there was a significant decrease in
the percent of neuronal membrane contacted by both F and S boutons
and a significant increase in F boutons displaying degeneration.
These results suggest that some neurotoxin-induced diseases of axons
are associated with alterations of synaptic complexes that may have
important implications for neuronal functioning
Kiss A, Borsosova D (1982) Morphological study on the central
subdivision of the rat hypothalamic ventromedial nucleus. Anat.Anz.
152:113-124
Abstract: Central subdivision of the rat hypothalamic
ventromedial nucleus (VMN) was examined with the transmission
electron microscope. This portion of VMN consists of densely packed
neuronal somata which are characterized by a large pale nucleus with
a prominent nucleolus, with clear cytoplasm containing many free
ribosomes and randomly distributed fragments of rough endoplasmic
reticulum, with small mitochondria and homogeneous lysosomes, with
well developed Golgi complex surrounded by a few clear and largely
2-3 dense-core vesicles of 90-110 nm in size and with nucleotid
bodies. Besides neuronal somata and their processes also astrocytes,
oligodendrocytes and Microglial
cells and their processes are often seen in this portion of VMN. In
the neuropil axo-somatic and axo-dendritici synapses,
capillaries, myelinated nerve fibers, nerve profiles filled with
dense-core vesicles and distal parts of ependymal tanycytic
processes are usually found in the central subdivision of VMN
Komuro T, Baluk P, Burnstock G (1982) An ultrastructural
study of neurons and non-neuronal cells in the myenteric plexus of
the rabbit colon. Neuroscience 7:1797-1806
Abstract: The
myenteric plexus of the rabbit colon showed a degree of structural
organization that was unusually high for the peripheral nervous
system, providing a basis for the complex integrative activity which
is known to occur. It resembled central nervous tissue in several
respects: a wide range of neuron types was present; the proportion
of glial cells to neurons was about 2:1; and there was a densely
packed, avascular neuropil, not penetrated by connective tissue.
Most neurons had at least one surface exposed to the extraganglionic
space. Clear evidence was obtained for spontaneous neuronal
degeneration. Three types of non-neuronal (glial) cells were
observed: Type 1, which was most common, contained many 10 nm
'gliofilaments' and resembled enteric glial cells or astrocytes in
the central nervous system; Type 2, composing about 5% of the glial
cells, had few filaments; Type 3 was seen only rarely, had a small
dark nucleus, little cytoplasm, may have been of extraganglionic
origin and resembled Microglia
of the central nervous system. Fibroblast-like cells were also
present in extraganglionic sites. Schwann cells could not be
identified within the myenteric ganglia
Leibnitz L, Bar B, Gunther L, Ludwig R, Hedlich A (1982) The
glia types inthe visual system of adult rats, their shape
variability, distribution patterns, and their lightoptically visible
contacts to other tissue structures. J.Hirnforsch.
23:225-238
Abstract: In silver impregnated coronal sections of
adult rat brains the glia types of the Corpus geniculatum laterale,
pars dorsalis (CGLd) an in area 17 were registered considering their
form variants (FV), their intraareal distribution and their light
optically demonstrable connexions to other tissue structures.
Compared with the shape-determining light optically visible
processes and perikarya, astrocytes show the lowest, Microglial
cells the greatest from variability. Transitional forms between the
three glia types were not detected, but between elongated astrocytes
and fiber astrocytes. An accumulation of elongated astrocytes, fiber
astrocytes, and oligodendrocytes was found in the lateral zone of
the CGLd, of protoplasmic astrocytes in the lateral and intermediary
zones and at the rostral and caudal poles of the griseum, too. In
the cortex distribution differences in the single laminae became
also evident. Astrocytes were most concentrated in L I,
oligodendrocytes and Microglia,
however, in L V. A few FV of the Microglia
were found to show a predominant localisation in specific laminae.
Neither the total glia number nor the single glia types correlate
with the neuron packing density. The frequency distribution of the
FV of oligodendroglia in the CGLd and the visual cortex is similar,
that of Microglia,
however, significantly deviating. Compared with the CGLd the
oligodendrocytes of area 17 have smaller somata. Astrocytes,
oligodendrocytes and Microglial
cells reveal structural contacts to different parts of the neurons,
to blood vessels and other glial cells, too. Contacts between
oligodendrocytes and Microglial
cells as well as astrocytes in satellite position could never be
observed. In the cortex a few FV of Microglia
show typical connexions
Murabe Y, Sano Y (1982) Morphological studies on neuroglia.
V. Microglial
cells in the cerebral cortex of the rat, with special reference to
their possible involvement in synaptic function. Cell Tissue Res.
223:493-506
Abstract: Electron-microscopic survey of selectively
stained Microglial
cells in the cerebral cortex of the rat reveals that the processes
of this cell type often encircle axo-dendritic synapses.
Enzyme-histochemical methods for thiamine pyrophosphatase (TPPase)
or nucleoside diphosphatase (NDPase) were used for the selective
marking of the Microglial
cells; TPPase and NDPase activities were observed in the plasma
membrane of Microglial
cells. The synapses
encircled by Microglial
processes displayed presynaptic structures containing round clear
vesicles (50 nm in diameter) and a prominent thickening of the
postsynaptic membrane. In vitro, the above-mentioned enzymatic
activities were completely suppressed by neuroactive agents such as
catecholamines and phenothiazine derivatives. Examination using
enzyme-histochemical techniques suggests that a single enzyme may be
responsible for both Microglial
cells in the normal central nervous tissue is discussed
Mize RR, Spencer RF, Sterling P (1981) Neurons and glia in
cat superior colliculus accumulate [3H]gamma-aminobutyric acid
(GABA). J.Comp Neurol. 202:385-396
Abstract: We have examined by
autoradiography the labeling pattern in the cat superior colliculus
following injection of tritiated gamma-aminobutyric acid (GABA).
Silver grains were heavily distributed within the zonal layer and
the upper 200 micrometer of the superficial gray. Fewer grains were
observed deeper within the superficial gray, and still fewer were
found within the optic and intermediate gray layers. The
accumulation of label was restricted to certain classes of neuron
and glia. Densely labeled neurons were small (8-12 micrometer in
diameter) and located primarily within the upper 200 micrometer.
Dark oligodendrocytes and astrocytes showed a moderate accumulation
of label while pale oligodendrocytes and Microglia
were unlabeled. Label was also selectively accumulated over several
other types of profile within the neuropil, including presynaptic
dendrites, axons, and axon terminals
Nadler JV, Perry BW, Gentry C, Cotman CW (1980) Degeneration
of hippocampal CA3 pyramidal cells induced by intraventricular
kainic acid. J.Comp Neurol. 192:333-359
Abstract: Degeneration of
hippocampal CA3 pyramidal cells was investigated by light and
electron microscopy after intraventricular injection of the potent
convulsant, kainic acid. Electron microscopy revealed evidence of
pyramidal cell degeneration within one hour. The earliest
degenerative changes were confined to the cell body and proximal
dendritic shafts. These included an increased incidence of lysosomal
structures, deformation of the perikaryal and nuclear outlines, some
increase in background electron density, and dilation of the
cisternae of the endoplasmic reticulum accompanied by detachment of
polyribosomes. Within the next few hours the pyramidal cells
atrophied and became electron dense. Then these cells became
electron lucent once more as ribosomes disappeared and their
membranes and organelles broke up and disintegrated. Light
microscopic changes correlated with these ultrastructural
observations. The dendritic spines and the initial portion of the
dendritic shaft became electron dense within four hours and
degenerated rapidly, whereas the intermediate segment of the
dendrites swelled moderately and became more electron lucent. No
degenerative changes were evident in pyramidal cell axons and
boutons until one day after kainic acid treatment. Less than one
hour after kainic acid administration, astrocytes in the CA3 area
swelled, initially in the vicinity of the cell body and mossy fiber
layers. It is suggested that the paroxysmal discharges initiated in
CA3 pyramidal cells by kainic acid served as the stimulus for this
response. Phagocytosis commenced between one and three days after
kainic acid administration, but remained incomplete at survival
times of 6-8 weeks. Astrocytes, Microglia,
and probably oligodendroglia phagocytized the degenerating material.
These results point to the pyramidal cell body and possibly also the
dendritic spines as primary targets of kainic acid neurotoxicity. In
conjunction with other data, they support the view that lesions made
by intraventricular kainic acid can serve as models of epileptic
brain damage
Sumner BE (1979) Ultrastructural data, with special reference
to bouton/glial relationships, from the hypoglossal nucleus after a
second axotomy of the hypoglossal nerve. Exp.Brain Res.
36:107-118
Abstract: The left hypoglossal nerve of adult male
albino rats was prevented from regenerating to the tongue after a
distal axotomy by implanting the proximal stump into normally
innervated left sternomasoid muscle. Eighty-four days after
implantation, the hypoglossal nerve was transected again and its
regeneration to the tongue unimpeded. From 8 to 70 days after this
second axotomy the left hypoglossal nuclei were processed for
quantitative ultrastructural analysis. The first aim of this study
was to compare regeneration success in the hypoglossal nucleus after
second axotomy with that accompanying outgrowth of the hypoglossal
nerve into denervated sternomastoid muscle. During quantitative
analysis a second aim developed, of elucidating bouton/glial
relationships. The second axotomy induced loss and return of
subsurface cisterns, dispersal and reassembly of Nissl substance,
increase and decrease of Microglial
numbers, slight further loss and partial return of boutons with
clear spherical vesicles and symmetrical synapses,
slight increase and decrease of boutons with clear flat vesicles and
symmetrical synapses,
regrowth of retracted dendrites and restoration of their synapses,
and gradual diminution of numbers of electron-dense neurones and
dendrites. Astrocytes remained hypertrophied throughout. When
compared with events in the hypoglossal nucleus accompanying
innervation of denervated sternomastoid muscle by the hypoglossal
nerve, the results suggest (1) that regeneration of the hypoglossal
nerve to its own tongue muscle instead of to a foreign muscle caused
no acceleration of recovery in the hypoglossal nucleus, and (2) that
the Microglial
response is dependent on nerve integrity and not on bouton behaviour
Chen DH (1978) Qualitative and quantitative study of synaptic
displacement in chromatolyzed spinal motoneurons of the cat. J.Comp
Neurol. 177:635-664
Abstract: Qualitative and quantitative
cytological evidences show a reduction in number and percentage of
coverage of terminals on chromatolyzed spinal motoneurons 4 to 90
days after severance of their axons in the ventral root. The
reduction in number and percentage of boutons on the surface
membrane is due to detachment of synapses.
This detachment is associated with changes in specialized regions
(synaptic complexes: Conradi, '69) of synapses
which involve disappearance of both pre-and postsynaptic membrane
thickenings and widening of the synaptic cleft (width of 400-1,400
A). The separation of terminals from surface membrane is also
associated with the presence of reactive astrocytes and Microglia.
Most areas of surface membrane bared of synaptic contact are
occupied by astrocytic processes. The astroglial responses coincide
with the loss of synapses.
Microglial
cells, although extending to neuronal surface membrane, cover only a
small portion of it. An extensive separation of boutons by Microglia
is not observed. Most Microglia
are seen located at some distance from surface membrane and are
frequently separated by sheets of astrocytic processes. Synaptic
restoration occurs by about 90 days after axotomy. Some motoneurons
show good recovery, while others show only a limited amount
Kreutzberg GW, Barron KD, Schubert P (1978) Cytochemical
localization of 5'-nucleotidase in glial plasma membranes. Brain
Res. 158:247-257
Abstract: By means of a cytochemical procedure
5'-nucleotidase activity is demonstrated electron microscopically.
The enzyme is present in plasma membranes of astrocytes,
oligodendroglial cells and Microglial
cells, but not in neuronal plasma membranes
Sturrock RR (1978) Development of the indusium griseum. II. A
semithin light microscopic and electron microscopic study. J.Anat.
125:433-445
Abstract: Neurogenesis and gliogenesis in the
indusium griseum were studied in semithin sections and with the
electron microscope. Immature neurons were present at birth, but
differentiated rapidly until, by 15 days, they appeared to be fully
differentiated. At birth 38% of glia were glioblasts, 47% were
immature astrocytes and 15% were mature Microglia.
Astrocyte differentiation appeared to occur earlier than in adjacent
white matter. In the adult, 57% of glia were astrocytes, 21% were
oligodendrocytes, and 22% were Microglia.
The volume density of neuronal nuclei did not change with age, but
the volume density of neuronal perikaryon decreased from 34% at
birth to 13% at 15 days, while the neuropil increased from 24% to
58%. Very few immature synapses
were present at birth, but by 5 days a number of axodendritic
synapses were present, and
these increased with age
Sumner BE (1977) Responses in the hypoglossal nucleus to
delayed regeneration of the transected hypoglossal nerve, a
quantitative ultrastructural study. Exp.Brain Res.
29:219-231
Abstract: Electron micrographs of the left hypoglossal
nucleus of adult male albino rats were quantitatively analyzed from
9-70 days after allowing the transected left hypoglossal nerve to
regenerate after an 84 day delay. Delay was achieved by implanting
the proximal stump into already innervated sternomastoid muscle,
where no regeneration occurred. Regeneration was then allowed by
denervating the sternomastoid. During the regenerative period the
initially high number of abnormally electron dense perikarya and
dendrites decreased to almost normal values, but no cell removal was
seen. This suggested that the degenerate appearance of many profiles
after prolonged prevention of regeneration, was reversible. The
neuropil bouton and dendrite counts, and the numbers of synapsing
boutons per dendrite, increased steadily to normal values from the
low values of suppressed regeneration. Somatic bouton frequencies,
even though already low, decreased further at 32 days, and later
increased but not to normal values. The decrease at 32 days
coincided with the loss of many subsurface cisterns, and dispersion
of Nissl substance, all suggestive of chromatolysis. Later the
subsurface cisterns and Nissl substance returned. It was suggested
that the delay of complete recovery of somatic bouton frequencies
might be because of lack of sensory information from the denervated
muscle into which the hypoglossal nerve was regenerating, or because
of abnormally low starting values for the recovery phase. Astrocyte
(or, occasionally Microglial)
sheaths persisted along bouton-free perikaryal surfaces
Sumner BE (1977) Ultrastructural responses of the hypoglossal
nucleus to the presence in the tongue of botulinum toxin, a
quantitative study. Exp.Brain Res. 30:313-321
Abstract: The
ultrastructural effects of local injection of botulinum toxin into
the left half of the tongue of the rat, were studied quantitatively
35 days postoperatively in the left hypoglossal nucleus. The results
showed (1) a decrease in somatic and neuropil bouton numbers because
of loss of boutons with symmetrical synapses
and clear spherical synaptic vesicles, (2) a decrease in the numbers
of dendrite profiles in the neuropil, (3) an increase in the
proportion of dendrites and boutons with unusual inclusions,
suggestive of profile retraction, (4) an increase in the proportion
of profiles which were unusually electron-dense, (5) an increase in
the amount of astrocyte, and a growth of astrocyte sheaths around
bouton-free neurone surfaces, (6) the presence of occasional
Microglia,
and (7) subastrocytic subsurface cisterns. Control rats injected
with boiled toxin had no responses except (3) and (4) above, and
then only to a modest extent, possibly due to mechanical damage of a
few axons or terminals at the time of injection, or to insufficient
inactivation of the toxin by boiling. The results were compared with
those at 35 days after axotomy, and it was concluded that botulinum
toxin, which interrupts neuromuscular transmission, elicits the same
responses in the hypoglossal neurones, as does transection of the
hypoglossal nerve, even though earlier studies had discovered no
glial replication after botulinum toxin, in contrast to axotomy
Cragg BG (1976) Ultrastructural features of human cerebral
cortex. J.Anat. 121:331-362
Abstract: Neuronal and glial elements
have been examined in the temporal or frontal cortex of four brains
with normal parenchyma. The identifying features recognized in
animal brains have been found valid in human cortex for stellate and
pyramidal neurons and their dendrites, spines, synapses,
initial segments of axons, nodes of Ranvier and axon terminals; also
for astrocytes, oligodendrocytes of various electron densities,
pericytes, blood vessels and basement lamina, and for the relation
of subarachnoid space to arterioles. However, most Microglial
cells have unexpectedly sparse and pale cytoplasm with few
organelles, and the distribution of glial nuclear chromatin is not
entirely in accordance with that described in animal brains.
Fusiform neurons have been identified, and their cytoplasm resembles
that of stellate cells. Peculiarities of human cortex include a
nuclear inclusion that is present in stellate neurons only. Two
neuronal cell-body profiles were myelinated, and a blood capillary
was seen to penetrate a neuron. Somatic spines were found
occasionally with or without synapses.
Ribosomes can be present in axons, espicially at nodes of Ranvier,
and a small portion of axon terminals contain a variety of dense
bodies of which some are derived from mitochondria. Endoplasmic
reticulum can occur in a compressed stack in neurons, and an unusual
vesicular organelle has been seen in dendrites, axons and somata.
Astrocytes as well as oligodendrocytes and occasional Microglial
cells act as satellites to neurons, and the exchange of a
membrane-bound body between a neuron and asatellite glial cell is
illustrated. Some dark pycnotic neurons were present, and it was
remarkable that a closely apposed neuron could be entirely normal.
These findings are compared with published descriptions of cortical
ultrastructure in the brains of laboratory animals
Lemkey-Johnston N, Butler V, Reynolds WA (1976) Glial changes
in the progress of a chemical lesion. An electron microscopic study.
J.Comp Neurol. 167:481-501
Abstract: The response of non-neuronal
cells in the brain to monosodium glutamate (MSG) was studied in the
neonatal mouse brain. Neurons rapidly degenerate in this
chemically-induced lesion, and the glia reflect and respond to their
early pyknosis and death. Astrocytic glia exhibit the most profound
responses in the form of degenerative nuclear and cytoplasmic
changes within 15 to 20 minutes after ingestion of MSG. After 6 to
12 hours, a large glial cell population, containing neuronal and
synaptic debris, can be seen. Recovery of severely damaged
astrocytes is unlikely. Further, evidence of multiplication of
uninjured cells to supply this observed repopulation was found.
Microglia
start to engulf debris at 6 to 12 hours and continue this process
through at least 48 hours. From 3 to 48 hours, a third cell type,
tentatively identified as a Gitter cell, is preminently involved in
phagocytosis of neuronal elements. Nuclei of these cells enlarge and
their parikarya become vastly expanded in a fashion typical of
Gitter cells. These cells appear to represent the transformed
Microglia.
Phagocytosis following a chemical lesion induced by glutamic acid, a
neurotransmitter substance, is exceedingly rapid in comparison to
that elicited by other types of lesions. Further, endogenous glial
cells cope with the cellular debris; no participation in this
process by hematogenous cells was observed
Sumner BE (1976) Quantitative ultrastructural observations on
the inhibited recovery of the hypoglossal nucleus from the axotomy
response when regeneration of the hypoglossal nerve is prevented.
Exp.Brain Res. 26:141-150
Abstract: Electron micrographs of the
left hypoglossal nucleus were quantitatively analyzed in adult rats
52 to 98 days after transection of the left hypoglossal nerve and
implantation of the proximal stump into the already innervated
ipsilateral sternomastoid muscle, a procedure which prevented the
transected nerve from regenerating. Many presynaptic boutons with
clear spherical synaptic vesicles and symmetrical synapses
were lost from the injured perikarya and dendrites. Some perikarya
and dendrites (and, rarely, boutons) became electron dense, and
astrocyte or Microglial
sheaths partly surrounded them. Numbers of dendrite profiles in the
neuropil decreased. These statistically significant effects
persisted throughout the postoperative period, whereas after axotomy
with unimpeded nerve regeneration, these features would have
returned to normal by 84 days postoperatively. It was therefore
suggested that their recovery depended upon successful regeneration
and reconnection of the hypoglossal nerve with the tongue.
Subsurface cisterns, and profiles containing unusual inclusions,
were numerically normal 52 to 98 days postoperatively, so it was
suggested that their early response and recovery after simple
axotomy might be entirely dependent on nerve disconnection and not
on nerve reconnection
Davidoff M, Galabov G (1975) [The postnatal development of
the hypoglossal nucleus in the rat]. Z.Mikrosk.Anat.Forsch.
89:615-631
Abstract: Using light and electron microscopy the
neurons, glial cells and capillaries in hypoglossal nucleus of the
rats have been examined up to 20 days after birth. The neuronal
nuclei are usually situated ecentrically. The mitochondria and
extensively developed Golgi-zones occupy the perinuclear region. The
microtubules and lysosomes become more numerous with aging. At the
earliest periods rough endoplasmic reticulum (ER) occupies the
neuronal periphery, whereas after 14th day it is extended to the
perinuclear region also. The ER forms elongated and concentric
lamellated bodies and subsurface cisternae. At this time nucleolus
like bodies are also numerous in the cytoplasm. After 4th and 6th
days the extensive growth of dendrites, containing many cell
organelles, and axons rich in microtubules are observed. Only at the
birthday do neurons contain glycogen deposit. After 1st day the
glycogen leaves the pericaryon, but it persists a long time in the
neuronal processes. The symmetrical and asymmetrical contacts are
characteristic for the examined period. The axo-somatic and
axo-dendritic synapses are
more abundant, but "double synapses"
are also established. More synaptic boutons possess besides synaptic
vesicles dense-core vesicles at the earlier periods. The quantity of
asymmetric synapses
increases with differentiation. Extensive cell degeneration has been
established between 8 and 18th days. At 4 and 6 days the glial cells
penetrate from subependymal layer and they have satellite neuronal
position. This is more pronounced between 14 and 18 days when the
oligodendrocytes are more numerous and active. At the same time
fibrous astrocyte like cells are appeared. Microglial
cells were not observed. Capillary differentiation, expressed by
changes of the endothelial cells, pericytes and connective tissue
cells, continues after birth also
Sumner BE, Sutherland FI (1973) Quantitative electron microscopy on the injured hypoglossal nucleus in the rat. J.Neurocytol. 2:315-328
Blinzinger K, Kreutzberg G (1968) Displacement of synaptic terminals from regenerating motoneurons by Microglial cells. Z.Zellforsch.Mikrosk.Anat. 85:145-157