Regulation of synaptic plasticity and cognitive functions by store-operated Orai1 channels

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Ca2+ signaling mediates many essential roles in neurons including transmitter release, synaptic plasticity, and gene transcription. In dendritic spines, which constitute the sites where excitatory synaptic input is received, Ca2+ elevations drive many forms of synaptic plasticity including long-term potentiation (LTP) and spine morphogenesis. The mechanism of LTP and its physiological consequences are of intense interest in neuroscience, driven by findings showing that it likely forms the neurochemical basis of learning and information storage in the brain and is altered by numerous neurodegenerative diseases, brain injuries, and drugs of abuse. However, although the physiological phenomenon of LTP is very well characterized, its underlying molecular mechanism is less understood. One area of uncertainty is the identity of the Ca2+ entry pathways involved in generating spine Ca2+ signals and how these pathways interface with downstream signaling systems. In this work, we will investigate the contributions of a relatively poorly understood Ca2+ influx pathway formed by store-operated Orai1 channels for cognitive function, dendritic spine Ca2+ signaling, and LTP. Orai1 channels have been extensively studied in immune cells where they stimulate processes ranging from Ca2+-dependent gene expression to secretion of inflammatory mediators. Although growing evidence indicates that Orai1 is highly expressed in the brain including in many regions critical for learning and memory, the properties of these channels and their physiological roles in the brain are poorly understood. We hypothesize that Orai1 channels are a key mechanism for generating Ca2+ signals in dendritic spines and make significant contributions to synaptically-evoked Ca2+ rises in spines to regulate synaptic plasticity and cognition. Using mice lacking Orai1 or its activators, STIM1 and STIM2, we will address this hypothesis through three specific goals: 1) evaluate the contributions of Orai1 channels for cognitive processes related to learning, memory, and sensorimotor function in mouse models. 2) investigate the physiological contributions of Orai1 channels for LTP, CaMKII activation, and insertion of AMPA receptors into postsynaptic densities, and 3) examine the role of Orai1 channels for Ca2+ signaling in dendritic spines following synaptic stimulation. Together, these studies will address the role of a novel Ca2+ entry pathway for synaptic plasticity and cognitive function, and ultimately facilitate efforts to target Orai1 channels for developing novel therapeutics for cognitive dysfunctions.