Ultrastructural studies of the hippocampus and the prefrontal cortex of rats were performed 7, 30, and 50 days after their damage by neurotoxicant trimethyltin chloride (TMT). Significant damage to ...neurons was observed in both brain structures. In the hippocampus, a large number of autophagosomes (0.9±0.1 per μm
2
) appeared in the soma of neurons, dendrites, and axons in 7 days after intoxication. In addition, we observed the appearance of hyperchromic neurons with abnormal structure of mitochondria. In the prefrontal cortex, damaged neurons also contained autophagosomes, but their number was significantly lower (0.3±0.1 per μm
2
). The number of autophagosomes decreased with increasing the time after TMT administration: 30 days after injection, the content of autophagosomes in the hippocampus was 0.10±0.01 per μm
2
, while in the prefrontal cortex, autophagosomes were no longer found. We hypothesized that autophagy in the hippocampus was not effective enough to prevent neuronal death caused by the neurotoxicant.
•TGF-β1 at a concentration of 10 ng/ml did not significantly affect the initial stage of LTP and substantially changed the distribution of synaptic AMPA receptors in response to tetanic ...stimulation.•After tetanization 90% of AMPA receptors were due to the postsynaptic density.•The distribution of AMPA receptors after LTP induction with the cytokine was close to their distribution in control synapses.•The normal distribution of AMPA receptors in spinous synapses provides stabilization of the potentiated synapses to retain LTP for a long time.
Using the methods of electrophysiology and immunohistochemistry, the effect of the transforming factor beta-1(TGF-β1), an anti-inflammatory cytokine, on the long-term post-tetanic potentiation (LTP) in CA1 field hippocampal slices and the distribution of the GluR1 subunit of the AMPA receptor has been studied.
It was shown that TGF-β1 at a concentration of 10 ng/ml did not significantly affect the initial stage of LTP and substantially changed the distribution of synaptic AMPA receptors in response to tetanic stimulation. Twenty five minutes after the tetanization, the main pool of AMPA receptors (90%) was due to the postsynaptic density (PSD). By contrast, LTP in the presence of TGF-β1 was accompanied by less pronounced changes in the distribution of AMPA receptors. Their localization in both pre- and postsynaptic regions remained nearly the same as that in the control. It may be suggested that the normal distribution of AMPA receptors in spinous synapses promotes the stabilization of potentiated synapses, thereby retaining LTP for longer terms.
We studied the effect of the mitochondrial calcium-dependent pore (MPT pore) inhibitor alisporivir (5 mg/kg per day for 4 weeks) on the parameters of calcium ion transport and the intensity of ...mitophagy in mitochondria of the heart and skeletal muscles of dystrophin-deficient C57BL/10ScSn-
mdx
mice. Alisporivir increased the rate of calcium uptake by skeletal muscle mitochondria of
mdx
mice, which was accompanied by changes in the level of the MCU and MCUb subunits of the calcium uniporter. At the same time, the intensity of calcium uniport in the heart mitochondria did not change. Alisporivir was found to reduce the expression of
Pink1
and
Parkin
genes regulating the intensity of mitophagy in skeletal muscles of
mdx
mice, but did not affect the expression of these genes in the heart. This effect of alisporivir was accompanied by fragmentation and a decrease in the mean size of organelles. Possible mitochondrion-related mechanisms of the protective effect of alisporivir on the skeletal muscle and heart cells are discussed.
The work shows the effect of the metabolic modulator uridine on the functioning and ultrastructure of heart mitochondria in dystrophin-deficient
mdx
mice. Intraperitoneal administration of uridine ...(30 mg/kg/day for 28 days) improved K
+
transport and increased its content in the heart mitochondria of
mdx
mice to the level of wild-type animals. This was accompanied by a significant decrease in the level of malondialdehyde and an increase in the number of mitochondria in the heart of
mdx
mice. At the same time, uridine did not affect the hyperfunctionality of mitochondria in
mdx
mice, which manifested in an increase in the calcium retention capacity. Nevertheless, we noted that uridine causes a significant decrease in the level of fibrosis in the heart of
mdx
mice, which attested to a positive effect of therapy.
A variety of localization and signaling properties of eight subtypes of metabotropic glutamate receptors (mGluRs) in the brain provide glutamate an important regulatory role in many processes, ...including neurodegeneration and repair of neuronal damage. To identify specific subtypes of mGluRs, which are involved in neurodegeneration process, we assessed expression levels of their genes under pathophysiological conditions. Using quantitative real-time RT-PCR analysis, we studied transcription levels of mGlu2-5 and mGlu7 genes in the hippocampus after its damage by neurotoxicant trimethyltin chloride (TMT) in Wistar rats. This organotin compound is known to cause neurodegeneration in the brain, especially in the hippocampus. Morphological studies confirmed neuronal damage in CA3-CA4 subfields of the hippocampus 6 weeks after the treatment with TMT. Step-through passive avoidance test revealed memory deterioration in rat-treated TMT. Interestingly, 3 and 6 weeks after the treatment with TMT, expression levels of the mGlu2 and mGlu7 genes were not changed in comparison to the control values while expression level of mGlu4 genes was upregulated throughout the whole studied period of TMT action. The dynamics of mGlu3 gene expression revealed the existence of neuroinflammation 3 weeks after the treatment with TMT, which was further confirmed by the upregulation of cyclooxygenase-2 gene expression. The expression level of mGlu5 receptors was downregulated 6 weeks after the treatment with TMT. Our results revealed a significant role of mGlu4, mGlu5, and mGlu3 receptors in the neurodegenerative/reparative processes in the hippocampus after the treatment with TMT. Ligands of these receptor subtypes can be, therefore, considered potential therapeutic targets for prevention or reduction of neurodegeneration.
We studied the prolonged action of kainic acid on glutamatergic neurons in the dorsal hippocampus and the endocannabinoid-dependent protection against neurodegeneration. The pyramidal neurons of the ...CA3 field of the hippocampus, as well as granular and mossy cells of the dentate gyrus were examined. Light and electron microscopy revealed substantial damage to the components of the protein-synthesizing (rough endoplasmic reticulum, Golgi apparatus, and polyribosomes) and catabolic (lysosomes, autophagosomes, multivesicular structures, and lipofuscin formations) systems in all cells. Pyramidal and mossy neurons die mainly by the necrotic pathway. The death of granular cells occurred through both apoptosis and necrosis. The most vulnerable cells are mossy neurons located in the hilus. Activation of the endocannabinoid system induced by intracerebral injection of URB597, an inhibitor of degradation of endocannabinoid anandamide, protected the normal structure of the hippocampus and prevented neuronal damage and death induced by KA.
The effect of the anti-inflammatory cytokine IL-10 on the ultrastructural distribution of AMPA receptor GluR1 subunit in CA1 field of cultured hippocampal slices was studied by using ...immunohistochemical technique. It was found that long-term posttetanic potentiation increased the content of GluR1 in the postsynaptic density of the axo-spinous synapse. Addition of IL-10 in concentrations of 1 and 10 ng/ml to the medium facilitated long-term posttetanic potentiation thereby changing the distribution of GluR1 in the spine: the number of receptors increased in the cytoplasm and decreased in the postsynaptic density. It is assumed that activation of neuronal IL-10 receptors affects the distribution of AMPA receptors in axo-spinous synapses of hippocampal field CA1 through interplay of intracellular signaling pathways, thereby participating in the mechanisms of synaptic plasticity under normal conditions.
We have previously demonstrated that the development of oxidative stress in some pathologies can be prevented by activation of the mitochondrial ATP-dependent potassium channel (mitoK
ATP
). Here we ...studied the effect of modulation of mitoK
ATP
on the development of mitochondrial and endothelial dysfunction in the medulla oblongata and myocardium of rats with experimental parkinsonism. It is known that uridine-5’-diphosphate, activator of mitoK
ATP
, does not penetrate the plasma membrane, but it can be synthesized in cells from exogenous uridine that is delivered into cells by special transport systems. Our results suggest that mitoK
ATP
is involved in the development of mitochondrial and endothelial dysfunction in experimental parkinsonism and prove the cardio- and neuroprotective effects of uridine.
The deposition of beta-amyloid (Aβ) in the brain is detected in Alzheimer’s disease and during ageing. Until now, ultrastructural studies of changes caused by Aβ in the dentate gyrus are very scarce. ...The effects of Aβ 1-42 injection into the CA1 field of rat hippocampus were studied by electron microscopy. In 2 weeks after injection of aggregated Aβ in low concentrations, destructive changes were seen in the structure of dentate gyrus cells, which consisted in a decrease in the number of dentate gyrus neurons and axo-dendritic synapses. These changes were accompanied by enlargement of the endoplasmic reticulum cisterns and widening of the active zones of synapses. Thus, injection of aggregated Aβ 1-42 into the hippocampus led to irreversible (a decrease in the number of neurons and axo-dendritic synapses, agglutination of synthetic vesicles) and adaptive changes (an increase in the sizes of endoplasmic reticulum cisterns and active zones of synapses) in dentate gyrus neurons aimed at the maintenance of functional activity of the nervous system.
Ultrastructure of the neuropil of the brain oculomotor nuclei was studied in mice after 30-day exposure to microgravity on Bion-M1 biosatellite and after 13-h exposure to Earth gravity. The number of ...axo-dendritic synapses in the neuropil of the oculomotor nucleus significantly decreased after the flight. Degenerated axon terminals containing conglomerates of presynaptic vesicles appeared. The number of synapses with high functional activity increased and the length of active zones of the axo-dendritic synapses significantly increased. The observed ultrastructural changes of the neuropil of the oculomotor nuclei of mice exposed to microgravity reflect the development of long-term deafferentation of the analyzed brain structures. These changes in the neuropil ultrastructure can determine the disturbances in the oculomotor system,
e.g.
development of atypical nystagmus under conditions of microgravity.
