Synaptic Homeostasis Modulated by Kv4

Kv4 调节的突触稳态

• 批准号: 10552698
• 负责人: SUSAN L TSUNODA
• 金额: $ 6.55万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10552698
• 关键词: Action Potentials; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-42; Animal Behavior; Animals; Back; Behavior; Behavioral; Biological Models; Brain; Brain region; Coupled; Defect; Development; Disease; Drosophila genus; Frequencies; Functional disorder; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Glutamates; Goals; Homeostasis; Human; Kv4 channel; Learning; Long-Term Potentiation; Mammals; Mediating; Memory; Modeling; Molecular; Multigene Family; Mutation; Nervous System; Neurologic; Neurons; Nicotinic Receptors; Output; Pathologic; Patients; Physiological; Physiological Processes; Play; Potassium Channel; Regulation; Reporting; Role; Seizures; Signal Transduction; Synapses; Synaptic plasticity; System; Temporal Lobe Epilepsy; Testing; Training; Up-Regulation; alpha-bungarotoxin receptor; autism spectrum disorder; cholinergic; cholinergic neuron; cognitive function; experience; genetic approach; in vivo; inhibitor; insight; nervous system disorder; neural; neuronal excitability; normal aging; novel; nuclear factors of activated T-cells; optogenetics; overexpression; prevent; response; synaptic function; tool; voltage

Kv4 channels have been shown to play important roles in modulating neural activity: regulating the integration of high-frequency trains of synaptic input, regulating backpropagating action potentials, and contributing to long-term potentiation. Consequently, mutations that affect Kv4 function/availability have been shown to result in spatial learning defects, seizure behavior, as well as temporal lobe epilepsy. We have recently shown that expression and turnover of Kv4 channels are also affected in three new contexts: in modulating cholinergic synaptic homeostasis, in response to over-expression of human Aβ42, and during normal aging. In the proposed studies, we investigate the mechanisms underlying Kv4 expression during cholinergic synaptic homeostasis (also referred to as synaptic scaling). Synaptic homeostasis is a form of plasticity that has been heavily studied in the last decade as a protective mechanism that counterbalances changes in global neural activity; this likely occurs during physiological processes, such as learning/memory and development, as well as during pathological conditions. We used Drosophila central neurons as a model, and showed that Drosophila α7 (Dα7) nAChRs are up-regulated after cholinergic blockade, thereby enhancing synaptic currents and providing a homeostatic response. We found that this homeostatic response triggered a novel regulatory mechanism –the up-regulation of Kv4 channels, which we showed prevents an “overshoot” of the homeostatic response. We further showed that the up-regulation of Kv4 channels is blocked by transcriptional inhibitors, and is dependent on Dα7 nAChRs and Ca2+ influx. Drosophila continues to be an ideal model system for these studies because of its cholinergic CNS, the genetic tools it offers, its less redundant genome (eg. there is only a single Drosophila NFAT and Kv4 gene, each of which represents a multi-gene family in mammals), and the ability to go from mechanisms of gene regulation to physiological relevance in the intact brain, and whole animal behavior. The proposed studies will apply new optogenetic approaches to elicit cholinergic synaptic homeostasis in vivo (Aim-1) –something that has not been explored in any system, and which would currently not be feasible in mammalian systems. We will examine underlying molecular mechanisms, including a novel relationship between α7 nAChRs and Kv4 channels (Aim-2), and inactivity-induced transcription of Kv4 (Aim-3) that is mediated by NFAT (Aim-4). We will also test all molecular mechanisms for their physiological relevance in identified neurons in the intact brain and behaving animal (Aims 4-5). Our studies are likely to reveal novel insights into the underlying mechanisms of cholinergic synaptic homeostasis.

Kv4 通道已被证明在调节神经活动中发挥重要作用： 突触输入高频序列的整合，调节反向传播动作电位，以及 有助于长期增强。因此，影响 Kv4 功能/可用性的突变已被 研究表明，它会导致空间学习缺陷、癫痫行为以及颞叶癫痫。我们有 最近表明，Kv4 通道的表达和周转也在三种新环境中受到影响： 调节胆碱能突触稳态，响应人类 Aβ42 的过度表达，并在 正常老化。在拟议的研究中，我们研究了 Kv4 表达的机制 胆碱能突触稳态（也称为突触缩放）。突触稳态是一种形式 可塑性在过去十年中作为一种平衡的保护机制得到了深入研究 整体神经活动的变化；这可能发生在生理过程中，例如学习/记忆 和发育以及病理条件下。我们使用果蝇中枢神经元作为模型， 并表明果蝇 α7 (Dα7) nAChR 在胆碱能阻断后上调，从而增强 突触电流并提供稳态反应。我们发现这种稳态反应触发了 新颖的调节机制——Kv4通道的上调，我们证明它可以防止“过度调节” 稳态反应。我们进一步表明 Kv4 通道的上调被阻断 转录抑制剂，并且依赖于 Dα7 nAChR 和 Ca2+ 流入。果蝇仍然是 这些研究的理想模型系统，因为它具有胆碱能中枢神经系统、它提供的遗传工具、它的较少 冗余基因组（例如，果蝇只有一个 NFAT 和 Kv4 基因，每个基因代表一个 哺乳动物的多基因家族），以及从基因调控机制到生理学的能力 完整大脑和整个动物行为的相关性。拟议的研究将应用新的光遗传学 体内诱导胆碱能突触稳态的方法（Aim-1）——尚未在 任何系统，目前在哺乳动物系统中不可行。我们将检查底层 分子机制，包括 α7 nAChR 和 Kv4 通道 (Aim-2) 之间的新关系，以及 由 NFAT (Aim-4) 介导的 Kv4 (Aim-3) 不活动诱导转录。我们还将测试所有分子 完整大脑和行为动物中已识别神经元的生理相关性机制 （目标 4-5）。我们的研究可能会揭示胆碱能潜在机制的新见解 突触稳态。