Laboratory of Extrasynaptic Signalling

Department of Molecular Neurobiology

Head: Alexey Semyanov, corr. member of the RAS
semyanov@ibch.ru

neurons, glia, brain

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The laboratory is engaged in research of cellular and molecular mechanisms of information coding in neurons and glia networks, which are the basis of learning and memory.

Researchers are solving the following tasks:
  • To study how internal factors (hormones, pregnancy, aging) and environmental factors (anthropogenic pollution, nutrition, microbiota) influence on the brain functions.
  • To study of neurodegenerative diseases, such as epilepsy, Alzheimer's disease, lateral amyotrophic sclerosis, Parkinson's disease.
  • Mathematical modeling of processes in the brain.
  1. Cell technologies. Studies using electrophysiological and optical methods of processes occurring in neuron-astrocytic cultures derived from animals or from human iPS cells.
  2. Work with brain sections. The use of electrophysiological (patch-clamp) and optical methods – two-photon laser scanning microscopy, FLIM, superresolution.
  3. In vivo studies. Optical imaging and electrophysiology in vivo, behavior.

All publications (show selected)

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Alexey Semyanov

Tonic GABAA conductance favors spike-timing-dependent over theta-burst-induced long-term potentiation in the hippocampus

Some neurotransmitters that escape the synaptic cleft or are released by astrocytes can target extrasynaptic receptors.  Extrasynaptic GABAA receptors mediate tonic conductances that reduce the excitability of neurons by shunting. As such, tonic GABAA conductances have minimal effects on spike-timing-dependent synaptic plasticity while strongly attenuating the plasticity evoked by EPSP bursts. Our findings shed light on how changes in tonic conductances can selectively affect different forms of learning and memory. These results may explain how different forms of memory are affected by increasing tonic GABAA conductances under physiological or pathologic conditions, as well as under the influence of substances that target extrasynaptic GABAA receptors (e.g., neurosteroids, sedatives, antiepileptic drugs, and alcohol).

Caloric restriction triggers morphofunctional remodeling of astrocytes and enhances synaptic plasticity in the mouse hippocampus

In collaboration with Bioengineering department,  Laboratory of bioengineering of neuromodulators and neuroreceptors

Calorie-restricted (CR) diet has multiple beneficial effects on brain function. Here we report morphological and functional changes in hippocampal astrocytes in 3-months-old mice subjected to 1 month of the diet. Whole-cell patch-clamp recordings were performed in the CA1 stratum (str.) radiatum astrocytes of hippocampal slices. The cells were also loaded with fluorescent dye through the patch pipette. CR did not affect the number of astrocytic branches but increased the volume fraction (VF) of distal perisynaptic astrocytic leaflets. The astrocyte growth did not lead to a decrease in the cell input resistance, which may be attributed to a decrease in astrocyte coupling through the gap junctions. Western blotting revealed a decrease in the expression of Cx43 but not Cx30. Immunocytochemical analysis demonstrated a decrease in the density and size of Cx43 clusters. Cx30 cluster density did not change, while their size increased in the vicinity of astrocytic soma. CR shortened K+ and glutamate transporter currents in astrocytes in response to 5 × 50 Hz Schaffer collateral stimulation. However, no change in the expression of astrocytic glutamate transporter 1 (GLT-1) was observed, while the level of glutamine synthetase (GS) decreased. These findings suggest that enhanced enwrapping of synapses by the astrocytic leaflets reduces glutamate and K+ spillover. Reduced spillover led to a decreased contribution of extrasynaptic N2B containing N-methyl-D-aspartate receptors (NMDARs) to the tail of burst-induced EPSCs. The magnitude of long-term potentiation (LTP) in the glutamatergic CA3–CA1 synapses was significantly enhanced after CR. This enhancement was abolished by N2B-NMDARs antagonist. Our findings suggest that astrocytic morphofunctional remodeling is responsible for enhanced synaptic plasticity, which provides a basis for improved learning and memory reported after CR.

Patterns of Calcium Dynamics in Brain Astrocytic Networks

Astrocytes encode the state of local neural environment in spatiotemporal patterns of Ca2+ activity. In turn, Ca2+ events in astrocytes trigger release of gliotransmitters, modulate synaptic plasticity and local blood flow via various mechanisms. The use of genetically encoded Ca2+ indicators has allowed to visualize astrocytic Ca2+ activity on multiple scales from thin distal processes to whole cell domains to cell networks. Interpretation of imaging data requires adequate techniques of data processing, including motion correction, denoising, signal separation to slow and fast components, segmentation of separate Ca2+ events, and revealing possible recurrent patterns in their initiation. Here we demonstrated that spontaneous Ca2+ activity in single astrocyte takes form of separate events, which primarily located in the periphery of astrocytic spatial domains. The Ca2+ events (yellow tinctures at the processed image) spanned across wide range of sizes and durations. The fluorescence amplitude, the rates of rise and decay within such Ca2+ events were linked to the local cell morphology (e.g. thickness of the process). At the network level, the Ca2+ activity was fluctuating, most of the population activity peaks was explained by appearance of large size events, engulfing whole astrocyte domains, rather than an increase in events frequency. The proposed techniques and experimental data can shed light on the principles that define the formation of spatiotemporal patterns of astrocytic Ca2+ activity and possible involvement of these patterns in cognitive tasks.

Publications

  1. Браже АР, Доронин МС, Попов АВ, Денисов Александро, Семьянов АВ (2019). Patterns of Calcium Dynamics in Brain Astrocytic Networks. Ross Fiziol Zh Im I M Sechenova 105 (11), 1436–1451

3D reconstruction of astrocytic processes

3D reconstruction of astrocytic processes was obtained using electron microscopy of series slices. Astrocytic processes consisted of branchlets, shafts-like structures containing organelles, and leaflets, thin organelle-free perisynaptic processes attached to the branchlets. We observed leaflets of different sizes and shapes and showed that leaflet enlargement may potentially prepare the space to accept ER cisterns and leaflet conversion to branchlets extensions. Was shown that number of glutamatergic synaptic contact to a leaflet is determined only by the leaflet size.

Publications

  1. Gavrilov N, Golyagina I, Brazhe A, Scimemi A, Turlapov V, Semyanov A (2018). Astrocytic coverage of dendritic spines, dendritic shafts, and axonal boutons in hippocampal neuropil. Front Cell Neurosci 12, 248