Store-Operated Calcium Channels in the Brain: Functions in Astrocytes and a Role in Learning and Memory


Store-operated Ca2+ entry (SOCE) is a principal mechanism for generating cellular Ca2+ signals. Store-operated Ca2+ release-activated Ca2+ (CRAC) channels serve an essential role in generating Ca2+ elevations needed for transcriptional, enzymatic, and secretory effector cascades in many cell types. CRAC channels, comprised of the ER Ca2+ sensor STIM and the plasma membrane Ca2+ channel Orai, were discovered in the immune system but have been increasingly recognized for widespread roles throughout the organism. Here, we investigated the functional roles of CRAC channels in the nervous system, with a specific focus on their role in the hippocampus for astrocyte physiology and animal behavior. 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. In the first part of this dissertation, we identified store-operated 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 neurons. Ca2+ elevations are essential for many neuronal processes that form the neurochemical basis of learning and information storage in the brain. CRAC channels are highly expressed in brain regions critical for learning, memory, and cognition, including the hippocampus. However, their role in mediating the Ca2+ signals driving learning and memory are not well understood. In the second part of this dissertation, we investigated the role of CRAC channels in regulating cognitive and behavioral functions using conditional Orai1 knockout mice. We showed that these mice are impaired in working, spatial, and associative memory tasks, suggesting that Orai1 channels play a role in processes essential for learning and memory. Together, these studies add new insight into the physiological functions of store-operated CRAC channels in the nervous system and the consequences of dysfunction in this Ca2+ signaling pathway.

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