Synaptic Homeostasis Modulated by Kv4

Kv4 调节的突触稳态

• 批准号: 10334459
• 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/10334459
• 关键词: Action Potentials; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-42; Animal Behavior; Animals; 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 structure; 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; neuronal excitability; normal aging; novel; nuclear factors of activated T-cells; optogenetics; overexpression; prevent; relating to nervous system; 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.

Kv 4通道已被证明在调节神经活动中起重要作用： 整合突触输入的高频序列，调节反向传播动作电位，以及 有助于长时程增强。因此，影响Kv 4功能/可用性的突变已经被发现。 显示出导致空间学习缺陷、癫痫发作行为以及颞叶癫痫。我们有 最近表明，Kv 4通道的表达和营业额也受到三种新情况的影响： 调节胆碱能突触稳态，响应于人Aβ42的过度表达，以及 正常老化。在所提出的研究中，我们研究了Kv 4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 可塑性在过去十年中作为一种平衡的保护机制得到了大量研究 全局神经活动的变化;这可能发生在生理过程中，如学习/记忆 和发展，以及在病理条件下。我们用果蝇的中枢神经元作为模型， 结果表明，果蝇α7（Dα7）nAChRs在胆碱能阻断后上调，从而增强了 突触电流并提供稳态反应。我们发现这种自我平衡反应引发了 一种新的调节机制-Kv 4通道的上调，我们发现它可以防止 自我平衡反应我们进一步表明，Kv 4通道的上调被阻断， 转录抑制剂，并依赖于Dα7 nAChR和Ca 2+内流。果蝇仍然是 这些研究的理想模型系统，因为它的胆碱能中枢神经系统，它提供的遗传工具，它的少 冗余基因组（例如，果蝇只有一个NFAT和Kv 4基因，每个基因代表一个 哺乳动物中的多基因家族），以及从基因调节机制到生理调节机制的能力。 与完整大脑和整个动物行为的关联性。拟议的研究将应用新的光遗传学 在体内引起胆碱能突触稳态的方法（Aim-1）--这在 任何系统，并且目前在哺乳动物系统中不可行。我们将研究潜在的 分子机制，包括α7 nAChRs和Kv 4通道之间的新关系（Aim-2），以及 由NFAT（Aim-4）介导的Kv 4（Aim-3）的失活诱导的转录。我们还将测试所有的分子 它们在完整脑和行为动物中识别的神经元中的生理相关性的机制 (Aims（见第4-5段）。我们的研究很可能揭示胆碱能的潜在机制的新见解， 突触稳态