Biol Cybern (2008) 98:61–74 DOI 10.1007/s00422-007-0196-7
ORIGINAL PAPER
Computational modeling of paroxysmal depolarization shifts in neurons induced by the glutamate release from astrocytes Alexander N. Silchenko · Peter A. Tass
Received: 31 July 2007 / Accepted: 12 October 2007 / Published online: 6 December 2007 © Springer-Verlag 2007
Abstract Recent experimental studies have shown that astrocytes respond to external stimuli with a transient increase of the intracellular calcium concentration or can exhibit selfsustained spontaneous activity. Both evoked and spontaneous astrocytic calcium oscillations are accompanied by exocytosis of glutamate caged in astrocytes leading to paroxysmal depolarization shifts (PDS) in neighboring neurons. Here, we present a simple mathematical model of the interaction between astrocytes and neurons that is able to numerically reproduce the experimental results concerning the initiation of the PDS. The timing of glutamate release from the astrocyte is studied by means of a combined modeling of a vesicle cycle and the dynamics of SNARE-proteins. The neuronal slow inward currents (SICs), induced by the astrocytic glutamate and leading to PDS, are modeled via the activation of presynaptic glutamate receptors. The dependence of the bidirectional communication between neurons and astrocytes on the concentration of glutamate transporters is analyzed, as well. Our numerical results are in line with experimental A. N. Silchenko (B) · P. A. Tass Institute of Neuroscience and Biophysics 3 - Medicine, Research Center Juelich, 52425 Juelich, Germany e-mail:
[email protected] P. A. Tass e-mail:
[email protected] A. N. Silchenko · P. A. Tass Virtual Institute of Neuromodulation, Research Center Juelich, 52425 Juelich, Germany P. A. Tass Institute of Neuromodulation, University of Cologne, 50924 Cologne, Germany P. A. Tass Brain Imaging Center West, Leo-Brandt-Street, 52425 Juelich, Germany
findings showing that astrocyte can induce synchronous PDSs in neighboring neurons, resulting in a transient synchronous spiking activity. Keywords Astrocyte · Glutamate release · Modeling · PDS 1 Introduction Traditionally, the numerically supeior glial cells are viewed to have inferior roles in the central nervous system (CNS), mainly providing an optimal environment for neurons (Coles and Orkand 1983). Their main function is supposed to be the clearance of the extracellular space (ECS) from glutamate, potassium and other neurotransmitters released during synaptic activity (Coles and Orkand 1983; Newman 2005; Danbolt 2001). However, recent experiments revealed the involvement of glial cells in the active control of neuronal activity and synaptic neurotransmission (Charles 1998; Haydon 2001; Newman and Zahs 1997; Oliet et al. 2001). It has been shown that glia responds to neuronal activity with an elevation of the internal Ca2+ concentration, in this way causing the release of chemical transmitters from the glial cells themselves and, in turn, involving it in a feedback regulation of the neuronal activity and synaptic strength (Araque et al. 1999; Haydon and Araque 2002; Kang et al. 1998). According to this concept the synapse is formed by three functional elements, the pre- and postsynaptic neurons and the surrounding astrocyte, a particular type of glial cells (Haydon and Araque 2002; Volterra and Meldolesi 2005). It is well known that one of the main functions of astrocytes is to keep a lowlevel concentration of glutamate in the extracellular space via its uptake (Danbolt 2001). On the other hand, recent experiments clearly demonstrated that astrocytes can release glutamate in a calcium-dependent manner in response to the neuronal activity (Parpura et al. 1994; Araque et al. 1998;
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Robitaille 1998; Montana et al. 2006). Moreover, astrocytes demonstrate spontaneous oscillations, which are independent from the neuronal spiking and trigger slowly decaying glutamate-induced currents in neurons (Parri et al. 2001; Nett et al. 2002; Aguado et al. 2002). Taken together, these facts let to suggest that astrocytes may modulate the synaptic strength and synaptic transmission via the regulation of the glutamate concentration in the synaptic cleft (Haydon and Araque 2002; Robitaille 1998). Moreover, recent studies of communication between astrocytes in the hippocampal dentate molecular layer and excitatory synapses on dentate granulle cells revealed the first evidence for a physiological control of synaptic activity via the exocytosis of glutamate from astrocytes (Jourdain et al. 2007). Astrocytic glutamate generates SICs mediated by the activation of N-methyl-D-aspartate (NMDA) receptors in pyramidal cells as shown by the recent in vitro studies (Angulo et al. 2004; Fellin et al. 2004). By means of a dual recording, synchronized SICs were detected in pyramidal cells, which were spaced by
