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，以及它与几种神经疾病的关系，已经得到了很好的证实。在过去的二十年里，一个重要的假说得到了支持，即电压门控离子通道(VGICs)的内在可塑性以及突触强度的可塑性可能是支持这些关键海马体功能的细胞机制。本项目将重点研究VGICs对海马锥体神经元内质网(ER)钙离子的渐进性释放或耗竭的可塑性。这项工作的总体主题是，从内质网释放钙触发固有神经元属性的可塑性，这反过来又作为印记r的细胞相关作用，作为一种稳态机制，以抵消改变的神经元兴奋性。最近，联合PI的一篇研究文章证明了超极化激活的非特定阳离子H电流中存在可塑性，以响应内质网储存库的耗尽，为这一探索性拨款提议提供了背景。在这里，我们打算追求这种形式的内在可塑性 更多细节，具体涉及内质网钙的分级释放，而不是通过耗尽内质网存储。此外，在多个VGIC中存在依赖活性的可塑性机制的推动下，我们还建议探索其他树突状VGIC，它们可能会随着内质网钙的消耗和钙的分级释放而改变。具体地说，我们建议观察A型钾电流，它调节树突的兴奋性，并已被证明经历了各种形式的活性依赖的可塑性。我们还旨在更好地理解这些不同形式的内在可塑性背后的机制，这些内在可塑性是由内质网钙的逐步释放或耗尽引起的。我们推测，内质网钙的渐进性释放诱导的内源性可塑性在记忆编码中发挥作用，而耗竭诱导的内源性可塑性将发挥神经保护机制，降低钙库耗竭后的兴奋性，这是通过病理条件下改变网络活动而触发的。 公共卫生相关性：内质网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型钾通道的树突可塑性。我们的实验将在树突状h和A型K+通道中提供可能的信号通路，将储备物枯竭与癫痫诱导的通道病变联系起来。

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.