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Contract number
11.G34.31.0012
Time span of the project
2010-2014

As of 30.01.2020

11
Number of staff members
33
scientific publications
7
Objects of intellectual property
General information

Name of the project: Brain extracellular matrix as a determinant of intercellular communications and a target for therapeutic treatment

Strategy for Scientific and Technological Development Priority Level: в


Goals and objectives

Research directions: Research of the role of brain extracellular matrix in regulating neural activity, learning and memory

Project objective: Research of new functions of brain extracellular matrix molecules


The practical value of the study

  • We have studied laws of neuron glial networks activity in primary hippocampal culture caused by matrix destruction
  • Our researchers have determined molecular mechanisms of provoked epileptomorphic activity at the level of ion channels and glutamate receptors.
  • The Laboratory has studied the role of extracellular matrix molecules in synaptic plasticity. It is possible that destruction of heparan sulfates leads to decrease of long-term potentiation using a mechanism depending on L-type calcium channels while destruction of chondroitin sulfate proteoglycan decreases the NMDA/AMPA current ratio in hippocampal CA1 pyramidal neurons in absence of change in membrane excitability.
  • Analysis has been conducted for synaptic and extrasynaptic signaling after fermented destruction of components of extracellular matrix in mice of wild type and brevican knockout mice
  • Approaches and methods have been developed for visualizing synaptic plasticity and associated changes in matrix.
  • Thin structure of extracellular matrix surrounding synapses on neuron dendrite has been determined
  • We have conducted quantitative modeling of synaptic dynamics using the mathematical model of four-component synapse
  • The Laboratory has proposed and researched the phenomenological model of astrocytic regulation of neural network activity.
  • We have analyzed behavior characteristic of a model of schizophrenia caused by blockade NMDA-receptors by the МК801 antagonist.
  • Our researchers have immunocytochemically discovered disruption of structure of extracellular matrix in the amygdala of the brain correlated with changed behavior of mice evaluated through behavioral tests of endophenotypes of schizophrenia-like behavior.
  • We have conducted transcriptome analysis of hippocampal tissue and hippocampal cells and found differences in the number of differentially expressed genes in vivo and in vitro.
  • It has been shown that destruction of hyaluronic acid causes activation of the cascade of supplemental reactions negatively affecting excitability of neurons and their network activity in vivo.
  • We have found interest of genes of synaptic joints, mitochondrial metabolism and ribosomal apparatus after destruction of hyaluronic matrix.

Implemented results of research:

  • We have created a series of viral vectors to visualize synaptic plasticity and for research of the role the molecular extracellular matrix LGI1 in epileptogenesis winch poses commercial interest in terms of researching this series viral vectors for visualization synaptic plasticity and for research of the role of extracellular matrix molecules in various laboratories.
  • We have created a mathematical model of four-component synapse to study synaptic dynamics that allows to forecast changes in brain activities to the fullest extent possible

Education and career development:

  • 1 doctoral dissertation and 8 candidate dissertations have been defended.
  • We have conducted scientific and pedagogical training professionals of postgraduate schools as well as the «Neurobiotechnologies» school of the Institute of Biology and Biomedicine of the Lobachevskiy Nizhniy Novgorod State University.

Organizational and structural changes:

  • The Neurosience center of the Lobacchevskiy Nizhniy Novgorod State University has been launched.
  • The Center of Translation Technologies of the Lobacchevskiy Nizhniy Novgorod State University has been launched.
  • The Center for Genetic Collections of Experimental Animals with SPF vivarium has been created.
  • We have created a network laboratory for molecular and cellular technologies in collaboration with the Privolzhskiy Research Medical University

Other results:

  • We have studied levels of genome expression in in vitro brain cells of mice and hippocampus of mice 2 hours after destruction of extracellular matrix. The cells have been cultivated on multielectrode matrices over a long time period. The research has shown absence of difference in gene expression level of subunits of AMR receptors providing   permeability for calcium ions, absence of difference in spatial distribution of AMP receptors permeable and non-permeable to calcium on membranes of neurons, decrease of activity of neurons in the culture and in mnestic function in mice. 2-3 days after injecting hyaluronidase by immunoblotting, we have found significant increase in synaptic GluA1 containing calcium-permeable AMPA-receptors compared to GluA2 containing AMPA-receptors. Increase in concentration of GluA1 containing calcium-permeable AMPA-receptors in the culture and the hippocampus tissue was accompanied by development of epileptiform activity of neuron networks in vitro, enhancement of   learning ability and memory, presence of audiogenic seizures in 50 per cent of the mice of the С57BL/6 line in vivo. The changes were transitory and were normalized 9-10 days after restoration of extracellular matrix.
  • Additionally, full genome transcriptome analysis of cells in hippocampal cultures 2 hours after destroying extracellular matrix has shown 1494 genes whose expression level was most prone to changes (log fold change ≥2.0). Of those genes, activation has been found for 811 genes and for 683 genes decreased mRNA level has been found.
  • We have identified functional groups of genomes that are structurally and functionally linked to (a) synaptic transmission and (b) ribosome functions and protein biosynthesis, and (c) processes of energetic metabolism localized in mitochondria whose expression change were caused by destruction of extracellular matrix of the brain
  • Transcriptome analysis of cells of hippocampal tissue has shown 2484 differentially expressed genes. Of those genes, activation has been found for 1282 genes and for 1202 genes decreased mRNA level has been found.
  • We have identified 5 functional clusters (genes of the Ca2+ binding EF-domain, genes coding EFG domains, genes coding actin binding proteins, genes coding proteins connected with biological rhythm and genes coding ubiquitination system protein)
  • Bioinformatical analysis of signal paths with participation of proteins for which differentially expressed genes were found has shown activation of genes that are structurally and functionally connected to signaling cascades of axonal growth; neuroinflammatory signaling cascade; signalling cascade caused by ephrin receptors; epithelial adherens junctions. Search for regulators of transcription of found differentially expressed genes has shown hypothetical activation regulators of transcription CREB1 and FGF2.
  • It is supposed that distant increase in activity of neurons in neuron networks leading to epileptic seizure like activity after destroying hyaluronan matrix is caused not by change in expression of proteins of calcium-permeable subunits of АМРА-receptors but by post-translation changes caused, for example, by hyaluronidases-dependent dysfunction of RNA-dependent adenosine deaminase (ADAR2). It is possible that editing the ADAR2 transcript by ADAR2 was disrupted by moving ADAR2 into cytoplasm or its disintegration upon change in intracellular signalling pathway caused by destruction of intracellular matrix. Discovery of mechanisms of disruption of RNA GluA2 subunits editing in the presence of homeostatic changes in activity of neural networks of hippocampus allows to view the ferment RNA-dependent adenosine deaminase (ADAR2) as a target regulatory impact in epilepsy therapy as well as, possibly, in other ischemic, inflammatory and neutodegenerative diseases. Moreover, proteins of inflammatory intracellular signalling pathways that are activated by destruction of intracellular matrix can play an important role in remote homeostasis.

Collaborations:

  • Privolzhskiy Research Medical University (Russia): joint grant from the Russian Foundation for Basic Research, joint research, student exchange,, scientific events, and publications
  • Hannover Medical School (Germany), German Center for Neurodegenerative Diseases (Germany): joint research, student exchange, scientific events and publications
  • European brain matrix network: joint scientific events and publications

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Hayani H., Song I., Dityatev A.
Increased excitability and reduced excitatory synaptic input into fast-spiking CA2 interneurons after enzymatic attenuation of extracellular matrix. Frontiers in Cellular Neuroscience 12: № 149 (2018).
Minge D., Senkov O., Kaushik R., Herde M.K., Tikhobrazova O., Wulff A.B., Mironov A., van Kuppevelt T.H., Oosterhof A., Kochlamazashvili G., Dityatev A., Henneberger C
Heparan Sulfates Support Pyramidal Cell Excitability, Synaptic Plasticity, and Context Discrimination. Cerebral Cortex 27(2): 903–918 (2017).
Korotchenko S., Cingolani L.A., Kuznetsova T., Bologna L.L., Chiappalone M., Dityatev A.
Modulation of Network Activity and induction of Homeostatic Synaptic Plasticity by Enzymatic Removal of Heparan Sulfates. Philosophical Transactions of the Royal Society B: Biological Sciences 19 (369(1654)) (2014).
Vedunova M., Sakharnova T., Mitroshina E., Perminova M., Pimashkin A., Zakharov Yu., Mukhina I., Dityatev A.
Seizure-Like Activity in Hyaluronidase Treated Dissociated Hippocampal Cultures. Frontiers in Cellular Neuroscience 7: 149 (2013).
Kazantsev V.B., Gordleeva S.Y., Stasenko S.V., Dityatev А.E.
Appearance of Multistability in a Neuron Model with Network Feedback. Journal of Experimental and Theoretical Physics Letters 96(11): 739–742 (2013).
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