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XXIII Congress of I.P. Pavlov Physiology Society
Interactive Realistic Model of Protoplasmic Astrocyte
L. P. Savtchenko*1, C. Henneberger*1,2,3, L. Bard*1, T. P. Jensen1, J. P. Reynolds1, I. Kraev4, M. Medvedev4, M. G. Stewart4, D. A. Rusakov1
1 UCL Institute of Neurology, University College London, UK;
2 Institute of Cellular Neuroscience, University of Bonn, Germany;
3 German Center of Neurodegenerative Diseases, Bonn, Germany;
4 The Open University, Milton Keynes, UK.
Electrically non-excitable astrocytes appear able in transducing, integrating and propagating physiological intracellular diffusion signals. Decrypting this type of signalling, however, poses a conceptual difficulty because it requires an understanding of molecular interactions in the massive morphological structure of nanoscale-thin leaf-like processes which constitute the bulk of astrocyte geometry. How a particular cell signalling engages a precise type of geometry remains therefore poorly understood.
There have been no attempts to develop an astrocyte model with such a spongy morphology even though this could provide the key to mechanistic insights into astrocytic physiology and Ca2+ signalling.
To understand the role of complex pattern in cell function we have adapted the NEURON modelling environment to build a simulation tool to produce different astrocyte models with the detailed morphology, membrane properties and known molecular signalling mechanisms. The tool enables to design a distributed Ca2+ homoeostasis mechanisms including diffusion, wave propagation, gap-junction escape or channel currents whereas the simulation environment also has the capability to mimic uncaging, membrane physiology, volume current injections or fluorescence recovery after photobleaching (FRAP) experiments in the 3D tissue volume containing the astrocyte.
In our illustration study, the tool generates astrocyte which has adapted the features of hippocampal protoplasmic astrocytes (area CA1) documented through a combination of experiments involving electrophysiology, two-photon excitation imaging, a FRAP super-resolution technique and quantitative electron microscopy. We demonstrate how simulations with the model could help to unveil some fundamental features of astrocytic morphology and Ca2+ signalling that are not accessible to direct experimental probing.
To our knowledge, this is the first attempt to have a full-scale tool for astroglia simulations, which we believe will attract significant interest among a broad audience of cell biologists and neuroscientists.
Modeling of Neural Networks with Tetrapartite Synapses
S.V.Stasenko1*, I.A.Lazarevich1, V.B.Kazantsev1, A.E. Dityatev1,2
1 Lobachevsky university (UNN), Russia;
2 German Center for Neurodegenerative Diseases, Magdeburg, Germany. * Presenting e-mail: [email protected]
Uncovering the key role of different brain cells and structures in information processing and health and disease is the main task of modern neuroscience. Many years neurons were considered as the key players in information processing. Recent experimental study has uncovered crucial role in information processing of extracellular matrix molecules and astrocytic cells activity [1-4] . The neuron-glial interaction is mediated by spillover (diffusion) of neurotransmitters in the extracellular space and their binding to astrocytic membrane receptors. For example, released D-serine and ATP from astrocyte after binding of neurotransmitter to astrocytic membrane receptors might induce currents through ionotropic receptors on the postsynaptic side as well as lead to long-term changes through activation of metabotropic receptors. Activation of kainite receptors by astrocytic glutamate induces axonal depolarization and reduction of AP generation threshold, and hence changes the properties of spontaneous IPSCs, namely increases their frequency and amplitude [3]. In a series of experimental investigation, the role of extracellular matrix (ECM) molecules in regulation of synaptic transmission and neuronal excitability was highlighted. It is assumed that ECM-mediated regulation mechanisms are involved in homeostatic modulation of neuronal activity on extended time scales [1,2]. ECM-induced homeostatic plasticity helps prevent the pathological hypo- and hyper-excitation of neurons which may cause dysfunction and cell death. For instance, an experimentally observed effect referred to as synaptic scaling helps neurons maintain the extent of their activity within a certain range under different inputs [5,6]. Besides the neuron-glial and ECM-neuron interaction pathways there also exists ECM-astrocyte interaction which format the structure in the brain - tetrapartite synapse . Activation of glial cells is not only elicited by the diffusing neurotransmitter, but also by ECM
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XXIII Congress of I.P. Pavlov Physiology Society
molecule production [1]. According to the experimental data the influence of ECM molecules on astrocytes is associated with the change in the number and properties of glial cells (specifically, changes in cellular morphology and intracellular pH [7]), which would in turn modulate the efficiency of neuron-glial interaction.
We present a computational model of neuronal network with tetrapartite synapse. The model describes the dynamics of excitatory and inhibitory neuron populations in the presence of glial and ECM regulations and based on mean-field approach. Neuron dynamics we modeled by Wilson-Cowan mean - field model [8]. The astrocyte is described by gliatransmitter concentrations depending on excitatory neuron population. We found that interaction between ECM, astrocytes and neuronal populations lead to spontaneous activity oscillations on extended timescales. The interaction parameters determine the oscillation period (hours to days) and their existence and switching to bistable regimes.
The research was supported by RFFI (#17-02-01103 A) References
1. Dityatev A, Rusakov DA. Molecular signals of plasticity at the tetrapartite synapse. Curr Opin Neurobiol. CURRENT BIOLOGY LTD; 2011;21: 353-359. Available: http://discovery.ucl.ac.uk/1056439/
2. Kazantsev V, Gordleeva S, Stasenko S, Dityatev A. A homeostatic model of neuronal firing governed by feedback signals from the extracellular matrix. PLoS One. 2012;7: e41646. doi:10.1371/journal.pone.0041646
3. Semyanov A, Kullmann DM. Kainate receptor-dependent axonal depolarization and action potential initiation in interneurons. Nat Neurosci. 2001;4: 718-23. doi:10.1038/89506
4. Min M, Melyan Z, Kullmann D. Synaptically released glutamate reduces gamma-aminobutyric acid (GABA) ergic inhibition in the hippocampus via kainate receptors. Proc Natl Acad Sci U S A. NATL ACAD SCIENCES; 1999;96: 9932-7. Available: http://discovery.ucl.ac.uk/119188/
5. Turrigiano G. Homeostatic signaling: the positive side of negative feedback. Curr Opin Neurobiol. Elsevier; 2007;17: 318-324. Available: http://www.ncbi.nlm.nih.gov/pubmed/17451937
6. Rich MM, Wenner P. Sensing and expressing homeostatic synaptic plasticity. Trends Neurosci. 2007;30: 119125. Available: http://www.ncbi.nlm.nih.gov/pubmed/17267052
7. Gottfried C, Cechin SR, Gonzalez MA, Vaccaro TS, Rodnight R. The influence of the extracellular matrix on the morphology and intracellular pH of cultured astrocytes exposed to media lacking bicarbonate. Neuroscience. 2003;121: 553-562. Available: http://linkinghub.elsevier.com/retrieve/pii/S0306452203005578
8. Wilson H, Cowan J. Excitatory and inhibitory interactions in localized populations of model neurons. Bio-phys J. 1972;12: 1-24.
Role of Extracellular Signaling in the Neocortical Development
Victor Tarabykin
Charité - Universitatsmedizin Berlin, Germany; UNN Institute of Neuroscience, Russia.
In the developing cerebral cortex different types of neuron and glial cells are born in a precise sequential manner from specialized radial glia progenitors. After leaving mitotic cycle, they migrate out of the germinative zone and initiate differentiation program. We identified a novel mechanism that controls cell identity in the developing cerebral cortex via "feedback" of secreted factors to neuronal progenitors. A defined set of secreted factors including neurotrophin-3, Sfrpl and Fgf9 were found to induce premature and excessive production of upper layer neurons at the expense of deep layer neurons on one hand and precocious generation of glial precursors on the other hand. This "feedback" is likely to act at the distal part of a radial glia process located in the area of young differentiating neurons. We suggest that various concentrations of secreted factors can be sensed by the radial glia process inducing cell fate switch. We identified non-canonical TrkC receptor as a major mediator of this extracellular signaling that controls cell fate switch in the developing neocortex.
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