Morphological profile determines the frequency of spontaneous calcium events in astrocytic processes

Abstract

Astrocytes express a complex repertoire of intracellular Ca2+ transients (events) that represent a major form of signaling within individual cells and in the astrocytic syncytium. These events have different spatiotemporal profiles, which are modulated by neuronal activity. Spontaneous Ca2+ events appear more frequently in distal astrocytic processes and independently from each other. However, little is known about the mechanisms underlying such subcellular distribution of the Ca2+ events. Here we identify the initiation points of the Ca2+ events within the territory of single astrocytes expressing genetically encoded Ca2+ indicator GCaMP2 in culture or in hippocampal slices. We found that most of the Ca2+ events start in thin distal processes. Our mathematical model demonstrated that a high surface-to-volume (SVR) of the thin processes leads to increased amplitude of baseline Ca2+ fluctuations caused by a stochastic opening of Ca2+ channels in the plasma membrane. Suprathreshold fluctuations trigger Ca2+-induced Ca2+ release (CICR) from the Ca2+ stores by activating inositol 1,4,5-trisphosphate (IP3) receptors. In agreement with the model prediction, the spontaneous Ca2+ events frequency depended on the extracellular Ca2+ concentration. Astrocytic depolarization by high extracellular K+ increased the frequency of the Ca2+ events through activation of voltage-gated Ca2+ channels (VGCC) in cultured astrocytes. Our results suggest that the morphological profile of the astrocytic processes is responsible for tuning of the Ca2+ event frequency. Therefore, the structural plasticity of astrocytic processes can be directly translated into changes in astrocytic Ca2+ signaling. This may be important for both physiological and pathological astrocyte remodeling.\n\nMain pointsO_LIMajority of spontaneous Ca2+ events start in thin astrocytic processes\nC_LIO_LIHigher surface-to-volume ratio of the process is responsible for larger intracellular Ca2+ fluctuations\nC_LIO_LILarger intracellular Ca2+ fluctuations trigger Ca2+-dependent Ca2+ release\nC_LI