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

Abstract

Running title: Morphology-dependent calcium activity in astrocytesMain points:• Majority of spontaneous Ca 2+ events start in thin astrocytic processes • Higher surface-to-volume ratio of the process is responsible for larger intracellular Ca 2+ fluctuations • Larger intracellular Ca 2+ fluctuations trigger Ca 2+ -dependent Ca 2+ release Russian Science Foundation . AbstractAstrocytes express a complex repertoire of intracellular Ca 2+ 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 Ca 2+ 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 Ca 2+ events. Here we identify the initiation points of the Ca 2+ events within the territory of single astrocytes expressing genetically encoded Ca 2+ indicator GCaMP2 in culture or in hippocampal slices. We found that most of the Ca 2+ 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 Ca 2+ fluctuations caused by a stochastic opening of Ca 2+ channels in the plasma membrane. Suprathreshold fluctuations trigger Ca 2+ -induced Ca 2+ release (CICR) from the Ca 2+ stores by activating inositol 1,4,5-trisphosphate (IP 3 ) receptors. In agreement with the model prediction, the spontaneous Ca 2+ events frequency depended on the extracellular Ca 2+ concentration.Astrocytic depolarization by high extracellular K + increased the frequency of the Ca 2+ events through activation of voltage-gated Ca 2+ channels (VGCC) in cultured astrocytes. Our results suggest that the morphological profile of the astrocytic processes is responsible for tuning of the Ca 2+ event frequency. Therefore, the structural plasticity of astrocytic processes can be directly translated into changes in astrocytic Ca 2+ signaling. This may be important for both physiological and pathological astrocyte remodeling.

Caloric restriction triggers morphofunctional remodeling of astrocytes and enhances synaptic plasticity in the mouse hippocampus

“…The VF of astrocyte fine processes was estimated as previously described 28,29,78 . The image containing the middle of astrocyte soma was selected in the z-stack.…”

Astrocytes dystrophy in ageing brain parallels impaired synaptic plasticity

“…However, a mass of tiny peripheral astrocytic processes, the leaflets, cannot be resolved with diffraction-limited optical methods (Gavrilov et al, 2018). To quantify age-related changes in peripheral and perisynaptic processes, we analysed their VF as previously described (Medvedev et al, 2014;Popov et al, 2020;Wu et al, 2019). The VF of optically unresolved processes was estimated as a ratio of fluorescence along the astrocytic anatomic domain cross-section to the maximal fluorescence of soma ( Fig.…”

“…It triggers secretion (Zorec et al, 2012), regulates local blood flow (Filosa et al, 2004;Marina et al, 2020), defines astrocyte morphological plasticity (Molotkov et al, 2013;Tanaka et al, 2013). On the other hand, astrocytic Ca 2+ activity depends on astrocyte morphology and intercellular gap-junction coupling (Semyanov, 2019;Wu et al, 2019). To test whether astrocyte atrophy in the aged brain affects Ca 2+ dynamics in the astrocytic network, we performed confocal Ca 2+ imaging in CA1 str.radiatum of mouse hippocampal slices loaded with membranepermeable Ca 2+ dye Oregon-Green 488 BAPTA-1 AM (OGB-1).…”

An astrocytic basis of caloric restriction action on the brain plasticity

“…Morphological remodeling and gap-junction uncoupling can affect Ca 2+ activity in the astroglial network Semyanov, 2019;Wu et al, 2019). We performed confocal imaging of astrocytes stained with membrane-permeable Ca 2+ dye, Oregon Green 488 BAPTA-1 AM (OGB, Fig.…”

“…The VF of astrocyte fine processes was estimated as previously described (Medvedev et al, 2014;Plata et al, 2018;Wu et al, 2019). The image containing the middle of astrocyte soma was selected in the z-stack.…”