CRAC channels regulate astrocyte Ca 2+ signaling and gliotransmitter release to modulate hippocampal GABAergic transmission

Astrocytes are the major glial subtype in the brain and mediate numerous functions ranging from metabolic support to gliotransmitter release through signaling mechanisms controlled by Ca Despite intense interest, the Ca influx pathways in astrocytes remain obscure, hindering mechanistic insights into how Ca signaling is coupled to downstream astrocyte-mediated effector functions. Here, we identified store-operated Ca release-activated Ca (CRAC) channels encoded by Orai1 and STIM1 as a major route of Ca entry for driving sustained and oscillatory Ca signals in astrocytes after stimulation of metabotropic purinergic and protease-activated receptors. Using synaptopHluorin as an optical reporter, we showed that the opening of astrocyte CRAC channels stimulated vesicular exocytosis to mediate the release of gliotransmitters, including ATP. Furthermore, slice electrophysiological recordings showed that activation of astrocytes by protease-activated receptors stimulated interneurons in the CA1 hippocampus to increase inhibitory postsynaptic currents on CA1 pyramidal cells. These results reveal a central role for CRAC channels as regulators of astrocyte Ca signaling, gliotransmitter release, and astrocyte-mediated tonic inhibition of CA1 pyramidal neurons.