Glutamate regulation of calcium and IP3 oscillating and pulsating dynamics in astrocytes

1 Glutamate regulation of calcium and IP3 oscillating and pulsating dynamics in astrocytes Maurizio De Pittà1, Mati Goldberg1, Vladislav Volman2,3, Hugues Berry4, Eshel Ben-Jacob1,2,* 1. School of Physics and Astronomy, Tel Aviv University, 69978 Ramat Aviv, Israel 2. Center for Theoretical Biological Physics, UCSD, La Jolla, CA 92093-0319, USA 3. Computational Neurobiology Lab, The Salk Institute, La Jolla, CA 92037, USA 4. Project-Team Alchemy, INRIA Saclay, 91893 Orsay, France *Corresponding author: eshel@tamar.tau.ac.il, Tel.: +972 3 640 7845 Fax: +972 3 642 5787 2 Abstract Recent years have witnessed an increasing interest in neuron-glia communication. This interest stems from the realization that glia participates in cognitive functions and information processing and is involved in many brain disorders and neurodegenerative diseases. An important process in neuron-glia communications is astrocyte encoding of synaptic information transfer – the modulation of intracellular calcium (Ca2+) dynamics in astrocytes in response to synaptic activity. Here, we derive and investigate a concise mathematical model for glutamate-induced astrocytic intracellular Ca2+ dynamics that captures the essential biochemical features of the regulatory pathway of inositol 1,4,5- trisphosphate (IP3). Starting from the well-known two-variable (intracellular Ca2+ and inactive IP3 receptors) Li-Rinzel model for calcium-induced calcium release, we incorporate the regulation of the IP3 production and phosphorylation. Doing so, we extend it to a three-variable model (which we refer to as the ChI model), that could account for Ca2+ oscillations with endogenous IP3 metabolism. This ChI model is then further extended into the G-ChI model to include regulation of the IP3 production by external glutamate signals. Compared with previous similar models, our three-variable models include a more realistic description of the IP3 production and degradation pathways, lumping together their essential nonlinearities within a concise formulation. Using bifurcation analysis and time simulations, we demonstrate the existence of new putative dynamical features. The cross-couplings between IP3 and Ca2+ pathways endow the system with self-consistent oscillatory properties and favor mixed frequency- amplitude encoding modes over pure amplitude-modulation ones. These and additional results of our model are in general agreement with available experimental data and may have important implications on the role of astrocytes in the synaptic transfer of information. Keywords: inositol 1,4,5-trisphosphate metabolism, calcium signaling, pulsating dynamics, information encoding, phase-locking 3 I. Introduction Astrocytes, the main type of glial cells in the brain, do not generate action potentials like neurons do, yet they can transfer information to other cells and encode information in response to external stimuli by employing “excitable”-like rich calcium (Ca2+) dynamics (Volterra and Meldolesi, 2005). Recognition of the potential importance of the intricate inter- and intra-cellular astrocyte dynamics has motivated in recent years, intensive experimental efforts to investigate neuron-glia communication. Consequently, it was discovered that intracellular Ca2+ levels in astrocytes can be regulated by synaptic activity (Wang et al., 2006; Pasti et al., 1997; Porter and McCarthy, 1996; Parpura et al., 1994; Dani et al., 1992). Responses to low-intensity synaptic stimulation or spontaneous astrocyte activity usually consist of spatially confined Ca2+ transients (Nett et al., 2002; Pasti et al., 1997; Porter and McCarthy, 1996). On the other hand, high-intensity synaptic activity or stimulation of adjacent sites within the same astrocytic process, are generally associated with Ca2+ oscillations (Zonta and Carmignoto, 2002) that can bring forth propagation of both intracellular and intercellular waves (Stout et al., 2002; Charles, 1998; Cornell-Bell et al., 1990). Concomitantly, elevation of cytoplasmic Ca2+ induces the release from astrocytes of several neurotransmitters (or “gliotransmitters”), including glutamate, ATP or adenosine (see Evanko et al., 2004 for a review). These astrocyte- released gliotransmitters feed back onto pre- and post-synaptic terminals. It implies that astrocytes regulate synaptic information transfer (Volman et al., 2007; Fellin et al., 2004; Araque et al., 1998). Astrocytes can also mediate between neuronal activity and blood circulation (Fellin and Carmignoto, 2004), thus extending neuron-astrocyte communications to the level of neuronal metabolism (Bernardinelli et al., 2004). The physiological meaning of astrocytic Ca2+ signaling remains currently unclear, and a long-standing question is how it participates in the encoding of synaptic information transfer (De Pittà et al., 2008a; 2008b; Volterra and Meldolesi, 2005). Some of the available experimental data suggest a preferential FM (f

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