Molecular Mechanisms Mediating Involvement of Glial Cells in Brain Plastic Remodeling in Epilepsy.

In this review we summarize published data on the involvement of glial cells in molecular mechanisms underlying brain plastic reorganization in epilepsy. The role of astrocytes as glial elements in pathological plasticity in epilepsy is discussed. Data on the involvement of aquaporin-4 in epileptogenic plastic changes and on participation of microglia and extracellular matrix in dysregulation of synaptic transmission and plastic remodeling in epileptic brain tissue are reviewed.

[Two-nuclear neurons: sincitial fusion or amitotic division].

In the review the history of research two-nuclear neurons is stated and two hypotheses about mechanisms of their formation are analysed: by sincitial fusion or amytotic divisions. The facts of discrepancy of the former orthodox cellular theory categorically denying possibility sincitial of communications in nervous system and of sincitial fusion neurons are mentioned. As an example results of ultrastructural researches of occurrence sincitium in a cortex of the big brain of rats, in autonomic ganglions, in hypocampus and a cerebellum of adult animals are presented. The video data of the sincitial fusion of live neurons and the mechanism of formation multinuclear neurons in tissue culture are analyzed. Existing data about amytotic a way of formation two-nuclear neurons are critically considered. The conclusion becomes, that the mechanism of formation two-nuclear neurons is cellular fusion. Simultaneously the review confirms our representations about existence in nervous system sincitial interneural communications.

[Fusion of brain neurons in rat embryos].

Syncytial interneuronal connections were studied in the sensomotor cortex and caudate nucleus of twenty 14-22 day rat embryos. It was shown that with the extremely weak development of glial processes, many neuronal bodies and their processes were in the direct contact with each other. The contacting membranes in these areas formed oblong and dot-like contacts resembling gap and tight junctions. As a result, the intercellular cleft experienced varicose-like deformations. In the area of contacts, barely visible membrane pores were formed that broadened to form large perforations. The perforation margins presented the rounded shape of fused plasma membranes of adjacent neurons. Inside the perforations, residual vesicular membranous bodies were formed. The areas of the paired membranes between perforations were fragmented, thus increasing the number of residual vesicles, until the neurons fused with each other completely by unifying the neuroplasm of contacting cells. The results of these studies suggest that that the fusion of neurons in vertebrate brain cortex and brainstem nuclei could occur not only in pathology, but also in normal animals at the stage of embryonic development.

In vitro effects of anandamide and prostamide e2 on normal and transformed nerve cells.

We studied the effects of endocannabinoid anandamide and its cyclooxygenase derivative prostamide E2 on cultured cerebellar granular cells and C6 glioma cells from rats. Prostamide E2 prevented apoptosis in cerebellar neurons induced by potassium deprivation of cultures, while anandamide had no neuroprotective properties. Prostamide E2 did not modulate the survival rate of glioma cells, while anandamide produced a cytotoxic effect. Our results indicate that cyclooxygenase transformation of anandamide is followed by the loss of antitumor activity of this agent. By contrast, prostamide E2 exhibited strong neuroprotective properties.

Antioxidant and neuroprotective properties of N-docosahexaenoyl dopamine.

N-Docosahexaenoyl dopamine exhibited antioxidant activity in the test with a stable oxygen radical galvinoxyl. This compound produced a dose-dependent protective effect on cultured granular cells from rat cerebellum under conditions of oxidative stress. N-Docosahexaenoyl dopamine decelerated the development of symptoms of Parkinson's disease in mice receiving neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

[Ischemic injury of the ultrastructure of neurons in organotypic hippocampal tissue culture]. / Ishemicheskie povrezhdeniia ul'trastruktury neironov v organotipicheskoi kul'ture tkani gippokampa.

An ultrastructural study of organotypic hippocampal explants subjected to the effect of ischemia for 30 min followed by a period of reoxygenation lasting for 20-24 hours, was performed. The data obtained indicate that ischemic injury of area CA1 neurons develops mainly as a necrosis. In addition, some neurons along with necrotic changes, demonstrate some signs of apoptosis, suggesting that the execution of its program may accompany these changes, thus leading the cells to the state of so-called apoptotic-necrotic continuum. On the other hand, the observed ultrastructural changes directed to metabolic activation and energy deficit compensation, may indicate the ability of neurons for realization of reparative processes following ischemic injury.

[Ultrastructural plasticity in the hippocampus organotypic tissue culture]. / Plasticheskie perestroiki ul'trastruktury gippokampa v organotipicheskoi kul'ture tkani.

Hippocampal cross sections of 7-9 day old rats were explanted onto semipermeable microporous membranes for 14-16 days followed by electron microscopic investigation. Besides the structures typical for adult hippocampus in vivo, substantial ultrastructural signs of metabolism and synaptic connections in explants were revealed: redistribution of polysomes and cisterns of granular endoplasmic reticulum, numerous pinocytotic invaginations, growth cones, somatic filopods, dotted (perforated) contacts, new formation of synapses and vacant postsynaptic sites. The data obtained indicate the active compensatory processes of plasticity, which ensure the maintenance of structure and function of hippocampal tissue in vitro.

[Changes in the configuration of the synaptic membranes in the human brain in aging and vascular pathology]. / Izmeneniia konfiguratsii sinapticheskikh membran v mozge cheloveka pri starenii i sosudistoi patologii.

The structure of synapses in the brain of persons who had died of aging and vascular disease was studied by electron microscopy which indicated synaptic contacts with the convex and concave surface of pre- and postsynaptic membranes. There were also synapses with more complicated alterations in the configuration of synaptic membranes. The functional significance of the phenomenon is discussed in the paper. It is assumed that the alterations in the curvature of synaptic membranes are manifestation of plasticity of a synapse and they are of compensatory value.

[The mechanism of the development of the synapse as the basis for its involution]. / Mekhanizm razvitiia sinapsa kak osnova ego involiutsii.

The electron microscopic investigation of human brain synaptic organization in normal aging and in ischemic heart pathology in different life periods was performed. A significant quantity of desmosome-like and mixed contacts was shown. Their ultrastructural organization was similar to that of developing synapses during prenatal ontogenesis and in newborn rats. The analysis of the experimental results suggests that an appearance of desmosome-like contacts in the human brain results from synapse involution. This is supported by the observation of formation of mixed contacts which may be a transitional stage between symmetrical or asymmetrical specialized synapse and desmosome. Thus, the mechanism of synaptic involution appears to be a mirror reflection of the mechanism of its development.

[Microvesicles in the developing synapses]. / Mikrovezikuly v razvivaiushchikhsia sinapsakh.

The sensomotor cortex and nucleus caudatus of the embryonal (14-22 days) and newborn rats have been investigated by electron microscopic method. There were described two groups of microvesicles (10-20 nm in diameter) with smooth and rough external surface. They differ from other vesicular components of the developing synapses (such as synaptic vesicles, vesicles of growing conus and other) by the minimal size, structure and localization. Microvesicles with the rough external surface are found only at that moment when the membranous specialization of the further synapse from desmosomes begins to form. They are found along the membranes of active contact zone and are correlated with the degree of differentiation of these membranes. Microvesicles with the smooth external surface are found during the all period of synaptogenesis. They are found either in presynaptic terminal freely or they are attached to presynaptic membrane where they form cluster of microvesicles and they can be found on the surface of synaptical vesicles too. In this article the functional role and genesis of microvesicles are discussed.

[Neurofibrillary changes in the nerve tissue of humans and animals]. / Neirofibrilliarnye izmeneniia v nervnoi tkani cheloveka i zhivotnykh.

Electron microscopy was employed to study neurofibrillary++ alterations in some parts of the brain of man aged 73 and 83 years (physiological ageing) and 36 to 80 years (vascular pathology) as well as in the spinal ganglion of dogs at different times after ischemia. Neurofibrillary++ alterations consisting in hyperplasia of microfilaments and formation of fibrillar bundles were recorded in both cases in nerve and glial cells and in their processes whereas in the human brain, they could be also detected in the intercellular space. Experimentally, filamentous hyperplasia in neurons was the most prevalent form whose intensity was related to the time elapsed after ischemia, attaining maximum in neurons with destructive processes. In human brain, filamentous alterations were not a permanent characteristic of neurons even on ageing. The greatest pleomorphism of fibrillar alterations could be observed in the soma of glial cells, in the processes of neurons and glia. Special emphasis should be laid on fibrillar bundles demonstrable in the intercellular space of human brain. Ultrastructure of the bundles was noted to be pleomorphic, which may be determined by their inconclusive genesis. It should be noted that fibrillar alterations in human brain are variable not only from case to case but also within the range of the same age. However, they are most remarkable in elderly and senile persons.

[Effect of vascular factors and aging on the ultrastructure of neurons of the human cerebral cortex]. / Vliianie sosudistogo faktora i stareniia na u'ltrastrukturu neironov kory bo'lshogo mozga cheloveka.

Neuronal ultrastructure of the frontal and temporal cerebral cortex has been studied in persons 36-, 39-, 50-, 70-year-old, died from the ischemic heart disease and 73-, 83-year-old, whose deaths are not connected with vascular pathology. The neurons can be divided into several groups, depending on osmiophilic degree of their nucleus and cytoplasm: I--electron-light, II--electron-opaque, III--with dark nucleus and light cytoplasm and IV--with light nucleus and dark cytoplasm. The protein-synthesizing apparatus (PSA) is subjected to the earliest and most essential disorders. Its changes in the I group of neurons at the age of 36-50 years are mainly of compensatory-adaptive character, while at the age of 73 and 83 years the dystrophic changes of the PSA result in hollowness of the cell, that evidently makes the base of the cell ageing mechanism. Presence of electron opaque neurons is not a sign of ageing, and depends on various pathology, in the given case on the ischemic heart disease, that causes certain vascular disorders in the brain. Variability of the ultrastructures of the electron opaque neurons and essential changes of some part of them, observed in the brain of the 72-year-old man confirm that the vascular factor is an important one in pathology of neurons. Dependence of lipofuscin appearance in neurons on the manifestation degree of the pathological process and ageing in them is discussed.

[Possible mechanisms of synapse formation during ontogenesis]. / Vozmozhnye mekhanizmy formirovaniia sinapsov v ontogeneze.

Electron microscopic investigation of synaptogenesis in the sensomotor cortex and in the caudate nucleus has been performed in the prenatal ontogenesis (16-22 days) and in newborn rats. The first immature synapses are demonstrated to appear beginning on the 16th day of embryogenesis. At the end of the prenatal development and especially in newborn animals desmosome-like, asymmetric and symmetric, mixed and complex forms of the synaptic contacts are revealed. As a result of the analysis performed on the ultrastructural organization of the contacts, a hypothesis explaining mechanisms of development of various elements of the synapses has been suggested. A part of the synaptic contacts of the asymmetric and symmetric types is supposed to be genetically programmed and membrane specialization of these contacts is formed earlier than synaptic vesicles appear. Other part of the synapses undergoes certain stages of differentiation before the functionally mature contact is formed. The initial stage in the synapses formation in formation of the desmosome-like junction. The second stage is appearance of synaptic vesicles in the area of this contact. The third stage includes development of pre- and postsynaptic membranous specialization and owing to this the contact acquires either asymmetric or symmetric appearance. For the ontogenetic periods investigated establishment of complex forms of the intercellular junctions (tangent, reciprocal, etc.) is specific; this evidently demonstrates certain plastic rearrangements in the synapses during the process of development.

[Various types of non-synaptic intercellular contacts in the developing brain of the rat]. / Razlichnye vidy nesinapticheskikh mezhkletochnykh kontaktov v razvivaiushchemsia mozge krysy.

Peculiarities of ultrastructural organization and localization of early forms of avascular nonsynaptic types of junctions formed in 14-18-day-old rat embryos have been studied; cerebral structures different in their phylogenic relations (the sensomotor cortex and nucleus caudatus) are taken as an example. Five main types of nonsynaptic intercellular junctions have been revealed: desmosome-like, gap, symmetric, asymmetric and mixed junctions. They differ by their ultrastructural organization. These types of junctions make the main types of contacts: soma-somatic, dendro-somatic, dendro-dendritic, axo-somatic, axo-dendritic. Desmosomes form the greatest number of the contacts. The earliest and the most primitive are gap junctions; they, evidently, reflect functional activity of desmosome-like junctions. The mixed junctions, perhaps, reflect the developmental stages of the intercellular contacts of transition from one type of junctions into another. Localization peculiarities of the nonsynaptic intercellular contacts are demonstrated: glomerule-like formations, establishment of numerous contacts looking like a successive chain, and so on. For some other indices a longer period of intercellular contact formation in the nucleus caudatus is noted, comparing the sensomotor cortex, though the latter is a newer structural cerebral formation from the phylogenic point of view.

[Changes in neurons of the cerebral cortex in senile dementia]. / Izmeneniia neironov kory polusharii mozga pri senil'noi dementsii.

Using light and electron microscopy, the frontal, temporal and parietal cortical neurons were studied in 10 cases of senile dementia. It was found that along with general age-specific disorders of the ultrastructure of neurons and glial cells (varying degrees of chromatolysis, accumulation of lipofuscin, mitochondrial changes) the examination revealed ultrastructural shifts which might be characteristic of senile dementia. They include rearrangement of nuclear chromatin, destruction of nuclear membrane with the subsequent vacuolization of the nucleus and karyolysis, the appearance of polymorphic fibrillar inclusions in the cytoplasm of neurons and gliocytes, as well as the disappearance of subsuperficial cysterns. Destructive processes were also attended by signs of compensatory changes, i.e. displacement of the nucleolus to the nuclear periphery, the development of desmosomophide contacts at the site of the neuron and glial satellite cell contact, the grouping of cells, and frequent fusion of the adjacent cellular elements.

Changes in neurons and interneural connections of the higher sections of the motor system in the progeny of alcoholized male and female rats.

We have studied the effects of long-term alcoholic intoxication of male and female rats on the structural development of the sensory motor cortex and the caudate nucleus in 21-day-old rats (their progeny). Using light microscopy and morphometry we observed a delay in the maturation of neurons and their dendrites, and also dystrophic changes in the nerve structures in the experimental animals. The morphological changes observed show that alcoholic intoxication of parents leads to negative effects on postnatal development of their progeny.