A Computational Model of Interactions Between Neuronal and Astrocytic Networks: The Role of Astrocytes in the Stability of the Neuronal Firing Rate

Recent research in neuroscience indicates the importance of tripartite synapses and gliotransmission mediated by astrocytes in neuronal system modulation. Although the astrocyte and neuronal network functions are interrelated, they are fundamentally different in their signaling patterns and, possibly, the time scales at which they operate. However, the exact nature of gliotransmission and the effect of the tripartite synapse function at the network level are currently elusive. In this paper, we propose a computational model of interactions between an astrocyte network and a neuron network, starting from tripartite synapses and spanning to a joint network level. Our model focuses on a two-dimensional setup emulating a mixed in vitro neuron-astrocyte cell culture. The model depicts astrocyte-released gliotransmitters exerting opposing effects on the neurons: increasing the release probability of the presynaptic neuron while hyperpolarizing the post-synaptic one at a longer time scale. We simulated the joint networks with various levels of astrocyte contributions and neuronal activity levels. Our results indicate that astrocytes prolong the burst duration of neurons, while restricting hyperactivity. Thus, in our model, the effect of astrocytes is homeostatic; the firing rate of the network stabilizes to an intermediate level independently of neuronal base activity. Our computational model highlights the plausible roles of astrocytes in interconnected astrocytic and neuronal networks. Our simulations support recent findings in neurons and astrocytes in vivo and in vitro suggesting that astrocytic networks provide a modulatory role in the bursting of the neuronal network.

[1]  Klaus Obermayer,et al.  From in silico astrocyte cell models to neuron-astrocyte network models: A review , 2018, Brain Research Bulletin.

[2]  L. Savtchenko,et al.  Regulation of rhythm genesis by volume-limited, astroglia-like signals in neural networks , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[3]  D. Attwell,et al.  Astrocyte calcium signaling: the third wave , 2016, Nature Neuroscience.

[4]  G. Dallérac,et al.  How do astrocytes shape synaptic transmission? Insights from electrophysiology , 2013, Front. Cell. Neurosci..

[5]  Khaleel Bhaukaurally,et al.  Glutamate exocytosis from astrocytes controls synaptic strength , 2007, Nature Neuroscience.

[6]  Tullio Pozzan,et al.  Prostaglandins stimulate calcium-dependent glutamate release in astrocytes , 1998, Nature.

[7]  Khaleel Bhaukaurally,et al.  Local Ca2+ detection and modulation of synaptic release by astrocytes , 2011, Nature Neuroscience.

[8]  H. Parri,et al.  Spontaneous astrocytic Ca2+ oscillations in situ drive NMDAR-mediated neuronal excitation , 2001, Nature Neuroscience.

[9]  S. Oliet,et al.  Organization, control and function of extrasynaptic NMDA receptors , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[10]  Frank Kirchhoff,et al.  Astrocytes control synaptic strength by two distinct v-SNARE-dependent release pathways , 2017, Nature Neuroscience.

[11]  Nicolas Liaudet,et al.  Three-dimensional Ca2+ imaging advances understanding of astrocyte biology , 2017, Science.

[12]  D E Postnov,et al.  Dynamical patterns of calcium signaling in a functional model of neuron–astrocyte networks , 2009, Journal of biological physics.

[13]  G. Turrigiano The Self-Tuning Neuron: Synaptic Scaling of Excitatory Synapses , 2008, Cell.

[14]  Todd A Fiacco,et al.  Multiple Lines of Evidence Indicate That Gliotransmission Does Not Occur under Physiological Conditions , 2018, The Journal of Neuroscience.

[15]  Alfonso Araque,et al.  Neuronal activity determines distinct gliotransmitter release from a single astrocyte , 2018, eLife.

[16]  Dmitri A Rusakov,et al.  Astrocytic GABA transporter activity modulates excitatory neurotransmission , 2016, Nature Communications.

[17]  Henry Markram,et al.  Neural Networks with Dynamic Synapses , 1998, Neural Computation.

[18]  Mark Ellisman,et al.  Protoplasmic Astrocytes in CA1 Stratum Radiatum Occupy Separate Anatomical Domains , 2002, The Journal of Neuroscience.

[19]  Philip G. Haydon,et al.  Astrocytic adenosine: from synapses to psychiatric disorders , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[20]  R. Westerink,et al.  Human iPSC‐derived neuronal models for in vitro neurotoxicity assessment , 2018, Neurotoxicology.

[21]  Eshel Ben-Jacob,et al.  Glutamate Mediated Astrocytic Filtering of Neuronal Activity , 2014, PLoS Comput. Biol..

[23]  Hugues Berry,et al.  Astrocyte Networks and Intercellular Calcium Propagation , 2019, Springer Series in Computational Neuroscience.

[24]  Romain Brette,et al.  Modeling Neuron–Glia Interactions with the Brian 2 Simulator , 2019, Springer Series in Computational Neuroscience.

[25]  C. J. Lee,et al.  GABA as a rising gliotransmitter , 2014, Front. Neural Circuits.

[26]  Andrew C. Charles,et al.  Intercellular Calcium Waves in Neurons , 1996, Molecular and Cellular Neuroscience.

[27]  Maurizio De Pittà,et al.  Gliotransmitter Exocytosis and Its Consequences on Synaptic Transmission , 2019, Springer Series in Computational Neuroscience.

[28]  N. Brunel,et al.  Astrocytes: Orchestrating synaptic plasticity? , 2015, Neuroscience.

[29]  Mahmood Amiri,et al.  Astrocyte- neuron interaction as a mechanism responsible for generation of neural synchrony: a study based on modeling and experiments , 2012, Journal of Computational Neuroscience.

[30]  Bertil Hille G protein-coupled receptor , 2009, Scholarpedia.

[31]  S. Oliet,et al.  Gliotransmitters Travel in Time and Space , 2014, Neuron.

[32]  Nicolas Liaudet,et al.  Astrocyte Ca2+ signalling: an unexpected complexity , 2014, Nature Reviews Neuroscience.

[33]  Ben A. Barres,et al.  Emerging roles of astrocytes in neural circuit development , 2013, Nature Reviews Neuroscience.

[34]  Denis Wirtz,et al.  Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes , 2017, Neuron.

[35]  F. Windels,et al.  Neuronal activity , 2006, Molecular Neurobiology.

[36]  Alexei Verkhratsky,et al.  Neuroglia: the 150 years after , 2008, Trends in Neurosciences.

[37]  M. Zonta,et al.  Cytosolic Calcium Oscillations in Astrocytes May Regulate Exocytotic Release of Glutamate , 2001, The Journal of Neuroscience.

[38]  Eshel Ben-Jacob,et al.  Sparse short-distance connections enhance calcium wave propagation in a 3D model of astrocyte networks , 2014, Front. Comput. Neurosci..

[39]  G. Perea,et al.  Astrocytes Potentiate Transmitter Release at Single Hippocampal Synapses , 2007, Science.

[40]  Hee-Sup Shin,et al.  Channel-Mediated Tonic GABA Release from Glia , 2010, Science.

[41]  Eric A Newman,et al.  Glial Cell Inhibition of Neurons by Release of ATP , 2003, The Journal of Neuroscience.

[42]  Kaiyu Zheng,et al.  ARACHNE: A neural-neuroglial network builder with remotely controlled parallel computing , 2017, PLoS Comput. Biol..

[43]  Steve M. Potter,et al.  An extremely rich repertoire of bursting patterns during the development of cortical cultures , 2006, BMC Neuroscience.

[44]  A. Araque,et al.  Astroglial excitability and gliotransmission: an appraisal of Ca2+ as a signalling route , 2012, ASN neuro.

[45]  Andrea Volterra,et al.  Title : Astrocyte Ca 2 + signalling : an unexpected complexity , 2022 .

[46]  Kerstin Lenk A Simple Phenomenological Neuronal Model with Inhibitory and Excitatory Synapses , 2011, NOLISP.

[47]  Frederico A. C. Azevedo,et al.  Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled‐up primate brain , 2009, The Journal of comparative neurology.

[48]  Philip G. Haydon,et al.  Astrocyte–Neuron Communications , 2013 .

[49]  Jarno M. A. Tanskanen,et al.  Burst analysis tool for developing neuronal networks exhibiting highly varying action potential dynamics , 2012, Front. Comput. Neurosci..

[50]  Jari Hyttinen,et al.  Network-Wide Adaptive Burst Detection Depicts Neuronal Activity with Improved Accuracy , 2017, Front. Comput. Neurosci..

[51]  A. Araque,et al.  Tripartite synapses: glia, the unacknowledged partner , 1999, Trends in Neurosciences.

[52]  Vincenzo Crunelli,et al.  ATP-Dependent Infra-Slow (<0.1 Hz) Oscillations in Thalamic Networks , 2009, PloS one.

[53]  Eshel Ben-Jacob,et al.  G Protein-Coupled Receptor-Mediated Calcium Signaling in Astrocytes , 2018, Springer Series in Computational Neuroscience.

[54]  E. Ben-Jacob,et al.  Coexistence of amplitude and frequency modulations in intracellular calcium dynamics. , 2008, Physical review. E, Statistical, nonlinear, and soft matter physics.

[55]  Manuel Roncagliolo,et al.  Glutamate released spontaneously from astrocytes sets the threshold for synaptic plasticity , 2011, The European journal of neuroscience.

[56]  G. Perea,et al.  Tripartite synapses: astrocytes process and control synaptic information , 2009, Trends in Neurosciences.

[57]  T. Fellin,et al.  Communication between neurons and astrocytes: relevance to the modulation of synaptic and network activity , 2009, Journal of neurochemistry.

[58]  Eshel Ben-Jacob,et al.  A Tale of Two Stories: Astrocyte Regulation of Synaptic Depression and Facilitation , 2011, PLoS Comput. Biol..

[59]  Liang Peng,et al.  Roles of astrocytic Na+,K+‐ATPase and glycogenolysis for K+ homeostasis in mammalian brain , 2015, Journal of neuroscience research.

[60]  F. Stephenson,et al.  The GABAA receptors. , 1995, The Biochemical journal.

[61]  Andrea Volterra,et al.  Gliotransmission: Beyond Black-and-White , 2018, The Journal of Neuroscience.

[62]  M Giugliano,et al.  Single-neuron discharge properties and network activity in dissociated cultures of neocortex. , 2004, Journal of neurophysiology.

[63]  Enzo Pasquale Scilingo,et al.  Novel Spiking Neuron-Astrocyte Networks based on nonlinear transistor-like models of tripartite synapses , 2013, 2013 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC).

[64]  Kira E. Poskanzer,et al.  A roadmap to integrate astrocytes into Systems Neuroscience , 2019, Glia.

[65]  Laura Ylä-Outinen,et al.  Simulation of developing human neuronal cell networks , 2016, Biomedical engineering online.

[66]  Andrea Volterra,et al.  What do we know about gliotransmitter release from astrocytes? , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[67]  Antoine Triller,et al.  GABAA Receptors: Post-Synaptic Co-Localization and Cross-Talk with Other Receptors , 2011, Front. Cell. Neurosci..

[68]  Rogier Min,et al.  The computational power of astrocyte mediated synaptic plasticity , 2012, Front. Comput. Neurosci..

[69]  S. Oliet,et al.  Long term potentiation depends on release of D-serine from astrocytes , 2009, Nature.

[70]  A. Araque,et al.  Dynamic signaling between astrocytes and neurons. , 2001, Annual review of physiology.

[71]  L. Roux,et al.  Over Astroglial Networks: a Step Further in Neuroglial and Gliovascular Interactions , 2022 .

[72]  Susanna Narkilahti,et al.  Effect of prolonged differentiation on functional maturation of human pluripotent stem cell-derived neuronal cultures. , 2018, Stem cell research.