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

Astrocyte store-operated Ca2+ entry controls gliotransmitter release to alter hippocampal excitability. A CRAC team for astrocytes Astrocytes are the most abundant glial cell type in the brain and release small molecules in a Ca2+-dependent fashion, such as ATP, that regulate neuronal excitability. Toth et al. found that Ca2+ release–activated Ca2+ (CRAC) channels comprising the Ca2+ sensor STIM1 and the Ca2+ channel Orai1 were a major route of Ca2+ entry into hippocampal astrocytes. Genetic ablation of either STIM1 or Orai1 in astrocytes decreased intracellular Ca2+ increases in response to the purinergic receptor agonists ATP or UTP or the protease-activated receptor agonist thrombin. Furthermore, astrocytes deficient in Orai1 showed reduced vesicle exocytosis and ATP release, as well as an inability to stimulate the excitability of hippocampal interneurons. These results suggest that enhancing CRAC channel activity in astrocytes could be a strategy to suppress neuronal excitability. 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 Ca2+. Despite intense interest, the Ca2+ influx pathways in astrocytes remain obscure, hindering mechanistic insights into how Ca2+ signaling is coupled to downstream astrocyte-mediated effector functions. Here, we identified store-operated Ca2+ release–activated Ca2+ (CRAC) channels encoded by Orai1 and STIM1 as a major route of Ca2+ entry for driving sustained and oscillatory Ca2+ 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 Ca2+ signaling, gliotransmitter release, and astrocyte-mediated tonic inhibition of CA1 pyramidal neurons.