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

Ca ~（2+）信号在神经元中起着许多重要作用，包括递质释放、突触传递、突触后应激和突触后应激。 可塑性和基因转录。在树突棘，这构成了网站的兴奋性 当突触输入被接收时，Ca 2+升高驱动许多形式的突触可塑性，包括长时程增强（LTP）和棘形态发生。LTP的机制及其生理意义 结果是神经科学的强烈兴趣，研究结果表明， 形成了大脑中学习和信息存储的神经化学基础， 许多神经退行性疾病、脑损伤和滥用药物。不过虽然 LTP的生理现象被很好地表征，其潜在的分子 机制了解较少。一个不确定的领域是钙离子进入途径的身份 参与产生脊柱Ca 2+信号以及这些途径如何与下游细胞相互作用。 信号系统。在这项工作中，我们将调查相对较差的 了解钙池操纵的Orai 1通道形成的钙内流途径对认知功能的影响， 树突棘Ca 2+信号传导和LTP。Orai 1通道已经被广泛研究， 免疫细胞，它们刺激从Ca 2+依赖性基因表达到 炎症介质的分泌。虽然越来越多的证据表明Orai 1是高度 在大脑中表达，包括在许多对学习和记忆至关重要的区域， 对这些通道及其在大脑中的生理作用知之甚少。我们 假设Orai 1通道是树突状细胞产生Ca 2+信号关键机制， 并对突触诱发的Ca 2+升高做出重要贡献，以调节 突触可塑性和认知。使用缺乏Orai 1或其激活剂STIM 1和STIM 2的小鼠， 我们将通过三个具体目标来解决这个假设：1）评估 与学习、记忆和感觉运动功能相关的认知过程的Orai 1通道 在小鼠模型中。2)研究Orai 1通道对LTP的生理贡献， CaMKII激活，AMPA受体插入突触后致密物，和3）检查 Orai 1通道在突触刺激后树突棘中Ca 2+信号传导的作用。 总之，这些研究将解决突触可塑性的一种新的钙离子进入途径的作用 和认知功能，并最终促进针对Orai 1通道的努力， 认知功能障碍的新疗法。

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.