Calcium store-induced intrinsic plasticity in the hippocampus

描述（由申请人提供）：哺乳动物海马体在学习和记忆的不同方面的作用及其与几种神经系统疾病的关系已得到充分证实。在过去的二十年里，一个突出的假说得到了广泛的关注，即电压门控离子通道（VGIC）的内在可塑性沿着突触强度的良好可塑性可能是这些关键海马功能的细胞机制。本研究将探讨海马锥体神经元内内质网（ER）中钙离子的梯度释放或耗竭对VGICs可塑性的影响。这项工作的总体主题是，钙从ER的释放触发内在神经元特性的可塑性，这反过来又作为记忆印迹的细胞相关物或作为抵消改变的神经元兴奋性的稳态机制。co-PI最近发表的一篇研究文章证明了超极化激活的非特异性阳离子h电流响应ER商店耗尽的可塑性的存在，为这一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， 更详细地，具体参考钙从ER的分级释放，而不是通过消耗ER储存。此外，在多个VGIC的活动依赖性可塑性机制的存在的动机，我们还建议探索其他树突状VGIC，可能会改变响应消耗以及从ER存储的钙的分级释放。具体来说，我们建议看看A型钾电流，它调节树突的兴奋性，并已被证明经历各种形式的活动依赖性可塑性。我们的目的也是为了更好地了解这些不同形式的内在可塑性诱导的梯度释放或消耗的钙从ER的机制。我们假设，内在可塑性诱导的钙从ER的梯度释放将在编码记忆中发挥作用，而消耗诱导的内在可塑性将作为一种神经保护机制，降低兴奋性消耗后的钙存储，这是通过改变网络活动在病理条件下触发。 公共卫生相关性：ER储存的耗尽与包括癫痫在内的几种神经系统疾病有关，并且在癫痫条件下观察到h型和A型钾通道中的树突可塑性。我们的实验将提供推定的信号通路连接存储耗尽癫痫诱导的通道病在树突状h和A型K+通道。

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. PUBLIC HEALTH RELEVANCE: Depletion of ER stores has been linked to several neurological disorders including epilepsy, and dendritic plasticity in h- and A-type potassium channels have been observed under epileptic conditions. Our experiments will provide putative signaling pathways linking store depletion to epilepsy-induced channelopathies in dendritic h and A-type K+ channels.