Calcium store-induced intrinsic plasticity in the hippocampus

描述（由申请人提供）：哺乳动物海马在学习和记忆的不同方面的作用，以及它与几种神经系统疾病的关系，已经得到了很好的证实。在过去的二十年中，一个重要的假设是，电压门控离子通道（vgic）的内在可塑性以及突触强度的可塑性可能是这些关键海马功能背后的细胞机制。本项目将重点研究海马锥体神经元内质网（ER）钙的逐渐释放或耗竭对vgic可塑性的影响。这项工作的总体主题是，钙从内质网释放触发神经元固有特性的可塑性，而这反过来又作为印痕的细胞关联或作为一种平衡机制来抵消神经元兴奋性的改变。最近的一篇研究文章表明，超极化激活的非特异性阳离子电流在响应ER存储耗尽时存在可塑性，为该探索性资助提案提供了背景。在这里，我们打算追求这种形式的内在可塑性

DESCRIPTION (provided by applicant): The role of the mammalian hippocampus in different aspects of learning and memory, and its relationship to several neurological disorders, is well established. A prominent hypothesis that has gained traction over the past two decades is that intrinsic plasticity of voltage-gated ion channels (VGICs) along with the well- established plasticity in synaptic strength could be the cellular mechanisms underlying these crucial hippocampal functions. This project will focus on plasticity of VGICs in response to graded release or depletion of calcium from the endoplasmic reticulum (ER) in hippocampal pyramidal neurons. The overall theme of this work is that release of calcium from the ER triggers plasticity of intrinsic neuronal properties, which, in turn, acts either as a cellular correlate of an engram r as a homeostatic mechanism to counteract altered neuronal excitability. A recent research article by the co-PIs demonstrating the existence of plasticity in the hyperpolarization-activated nonspecific-cationic h current in response to the depletion of ER stores provides the background for this exploratory grant proposal. Here, we intend to pursue this form of intrinsic plasticity in greater detail, with specific reference to graded release of calcium from the ER, rather than through depletion of ER stores. Furthermore, motivated by the existence of activity-dependent plasticity mechanisms in multiple VGICs, we also propose to explore other dendritic VGICs that may change in response to depletion as well as graded release of calcium from the ER stores. Specifically, we propose to look at the A-type potassium current, which regulates dendritic excitability and has been demonstrated to undergo various forms of activity- dependent plasticity. We also aim to arrive at a better understanding of the mechanisms underlying these different forms of intrinsic plasticity induced by graded release or depletion of calcium from the ER. We postulate that intrinsic plasticity induced by graded release of calcium from the ER would play a role in encoding memory, whereas depletion-induced intrinsic plasticity would act a neuroprotective mechanism that reduces excitability after depletion of calcium stores, which is triggered through altered network activity during pathological conditions.