Biophysically based Computational Models of Astrocyte ~ Neuron Coupling and their Functional Significance

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Computational aspects of astrocytic Ca2+ signaling. (A) Scheme of IP3-mediated Ca2+-induced Ca2+ release in the astrocyte. Calcium and IP3 signals are controlled by synaptic glutamate through metabotropic glutamate receptor- (mGluR-) PLCβ-mediated IP3 production (see text for details). (B) IP3 and Ca2+ signals can be envisioned to encode incoming synaptic activity through frequency and amplitude of their oscillations. Astrocytes could thus encode synaptic information either by modulations of the amplitude (AM), the frequency (FM), or both (AFM) of their Ca2+ oscillations. (C) Simulated Ca2+ and IP3 patterns in response to sample synaptic glutamate release (Glu) in a model astrocyte (De Pittà et al., 2009a,b) reveals that IP3 signals could be locked in the AFM-encoding independently of the encoding mode of the associated Ca2+ signals. This feature could allow the astrocyte to optimally integrate synaptic stimuli. (D, top) Simulated Ca2+ (black trace) and IP3 (green trace) signals in the same astrocyte model as in (C), and associated rates of IP3 production (prod.) and degradation (degr.) (middle panels, dashed black lines) in response to two consecutive synaptic glutamate release events (bottom panel, Glu). The analysis of the contributions of different enzymes to IP3 signaling (solid colored traces; cyan: PLCβ ; pink: PLCδ ; orange: IP-5P; and purple: IP3-3K) reveals dynamical regulation by Ca2+ of different mechanisms of IP3 production/degradation which could ultimately underlie dynamical regulation of astrocyte processing of synaptic stimuli. (E) Simulated propagation of Ca2+ waves in a heterogeneous linear chain composed of both FM (red traces) and AFM (green traces) astrocytes reveals that encoding of synaptic activity (STIMULUS) could change according to cell location along the chain. Adapted from Goldberg et al. (2010).
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Astrocytes regulate presynaptic transmission and postsynaptic excitability at glutamatergic synapse. Following successful vesicular fusion, a fraction of released glutamate can spill over and reach metabotropic glutamate (mGlu) receptors on the membrane of adjacent astrocyte. Glutamate activation of astrocytic mGlu receptors activates a cascade of biochemical events that culminates in elevation of inositol trisphosphate (IP3) and increased intra-astrocytic free calcium concentration. Calcium causes a release of astrocytic glutamate (a process termed gliotransmission) which can bind mGlu receptors on presynaptic membrane and/or NMDA receptors on postsynaptic side, thus modulating the probability of synaptic transmitter release (PRELEASE) and/or postsynaptic excitability. For more quantitative details regarding the process of astrocyte modulation of synaptic transmission, see De Pitta et al. (2011).
Review
13 August 2012
Computational models of neuron-astrocyte interaction in epilepsy
Vladislav Volman
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Terrence J. Sejnowski

Astrocytes actively shape the dynamics of neurons and neuronal ensembles by affecting several aspects critical to neuronal function, such as regulating synaptic plasticity, modulating neuronal excitability, and maintaining extracellular ion balance. These pathways for astrocyte-neuron interaction can also enhance the information-processing capabilities of brains, but in other circumstances may lead the brain on the road to pathological ruin. In this article, we review the existing computational models of astrocytic involvement in epileptogenesis, focusing on their relevance to existing physiological data.

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