Abstract
Fluctuations of cytosolic Ca2+ concentration in astrocytes are regarded as a critical non-neuronal signal to regulate neuronal functions. Although such fluctuations can be evoked by neuronal activity, rhythmic astrocytic Ca2+ oscillations may also spontaneously arise. Experimental studies hint that these spontaneous astrocytic Ca2+ oscillations may lie behind different kinds of emerging neuronal synchronized activities, like epileptogenic bursts or slow-wave rhythms. Despite the potential importance of spontaneous Ca2+ oscillations in astrocytes, the mechanism by which they develop is poorly understood. Using simple 3D synapse models and kinetic data of astrocytic Glu transporters (EAATs) and the Na+/Ca2+ exchanger (NCX), we have previously shown that NCX activity alone can generate markedly stable, spontaneous Ca2+ oscillation in the astrocytic leaflet microdomain. Here, we extend that model by incorporating experimentally determined real 3D geometries of 208 excitatory synapses reconstructed from publicly available ultra-resolution electron microscopy datasets. Our simulations predict that the surface/volume ratio (SVR) of peri-synaptic astrocytic processes prominently dictates whether NCX-mediated spontaneous Ca2+ oscillations emerge. We also show that increased levels of intracellular astrocytic Na+ concentration facilitate the appearance of Ca2+ fluctuations. These results further support the principal role of the dynamical reshaping of astrocyte processes in the generation of intrinsic Ca2+ oscillations and their spreading over larger astrocytic compartments.
Highlights
Over the past three decades, astrocytes have emerged as crucial regulators of synaptic function (Zhang et al, 2016)
To simulate Ca2+ oscillations in real astrocyte processes, we used the saturated reconstruction of a 1,500 μm3 volume of mouse neocortex (Kasthuri et al, 2015)
We explored volumes of 1.2 × 1.2 × 1.2 μm around these synapses to investigate the potential of astrocytic processes to readout synaptic activity
Summary
Over the past three decades, astrocytes have emerged as crucial regulators of synaptic function (Zhang et al, 2016). Many of these regulatory functions operate by controlling the extracellular concentration of various substances pivotal to synaptic activity (Somogyi et al, 1990; Harris et al, 1992; Rusakov et al, 1997, 1998, 1999; Rusakov and Kullmann, 1998a,b; Araque et al, 1999; Bergles et al, 1999; Ventura and Harris, 1999; Newman, 2004; Matsui et al, 2005; Savtchenko and Rusakov, 2007; Heller et al, 2020) One of such classical astrocyte-mediated regulatory function is the uptake of synaptically released glutamate. EAAT-mediated Glu/Na+ symport may give rise to local Ca2+ fluctuations
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