Spontaneous Ca²⁺ Fluctuations Arise in Thin Astrocytic Processes With Real 3D Geometry

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.