Activity-Dependent Regulation of Kv4 Channels

Kv4 通道的活动依赖性调节

基本信息

批准号：
10176513
负责人：
SUSAN L TSUNODA
金额：
$ 35.77万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176513
关键词：
Action Potentials Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-42 Animal Behavior Behavior Biological Models Brain Brain region Chick Coupled Defect Development Disease Drosophila genus Frequencies Funding Gene Expression Regulation Genes Genetic Genetic Transcription Genome Glutamates Goals Homeostasis Human Kv4 channel Learning Long-Term Potentiation Mammals Manuscripts Mediating Memory Modeling Molecular Multigene Family Mutation Nerve Block Neurologic Neurons Nicotinic Receptors Pathologic Pathway interactions Patients Physiological Physiological Processes Play Potassium Channel Regulation Reporting Rodent Role Seizures Signal Transduction Structure of ciliary ganglion 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 genetic manipulation in vivo in vivo Model inhibitor/antagonist insight neuronal excitability normal aging novel nuclear factors of activated T-cells optogenetics overexpression prevent relating to nervous system response synaptic function tool voltage

项目摘要

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. In the last funding period, we showed that expression and turnover of Kv4 channels are 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. Synaptic homeostasis/scaling 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 eventually, 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. Our studies are likely to reveal important 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，以及经测试，影响 Kv4 功能/可用性的突变已被证实。最后显示会导致空间学习缺陷、癫痫行为以及颞叶癫痫。在资助期间，我们发现 Kv4 通道的表达和周转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，并在在正常衰老过程中，我们研究了 Kv4 表达的机制。胆碱能突触稳态。突触稳态/缩放是可塑性的一种形式，受到很大影响。过去十年作为一种平衡全球神经活动变化的保护机制进行了研究；这可能发生在生理过程中，例如学习/记忆和发育，以及在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我们发现这种稳态反应触发了一种新的调节机制—— 我们证明了 Kv4 通道的上调可以防止稳态反应的“过度调节”。我们进一步表明 Kv4 通道的上调被转录抑制剂阻断，并且依赖于 Dα7 nAChR 和 Ca2+ 流入的果蝇仍然是这些的理想模型系统。研究因其胆碱能中枢神经系统、它提供的遗传工具、其冗余基因组较少（例如，只有单个果蝇 NFAT 和 Kv4 基因，每个基因代表哺乳动物中的一个多基因家族），以及从基因调控机制到完整大脑的生理相关性的能力，最终，拟议的研究将应用新的光遗传学方法来引发胆碱能。体内突触稳态（Aim-1）——尚未在任何系统中探索过的东西，这将是目前在哺乳动物系统中不可行，我们将检查潜在的分子机制，包括 α7 nAChR 和 Kv4 通道 (Aim-2) 之间的新关系，以及 Kv4 不活动诱导的转录 (Aim-3) 由 NFAT (Aim-4) 介导我们还将测试其生理学的所有分子机制。我们的研究可能揭示完整大脑中已识别神经元的相关性。胆碱能突触稳态的潜在机制。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cholinergic Synaptic Homeostasis Is Tuned by an NFAT-Mediated α7 nAChR-Kv4/Shal Coupled Regulatory System.

胆碱能突触稳态由 NFAT 介导的 α7 nAChR-Kv4/Shal 耦合调节系统调节。

DOI：
发表时间：
2020
期刊：
影响因子：
8.8
作者：
Eadaim, Abdunaser;Hahm, Eu;Justice, Elizabeth D;Tsunoda, Susan
通讯作者：
Tsunoda, Susan

Inactivity-induced increase in nAChRs upregulates Shal K(+) channels to stabilize synaptic potentials.

不活动引起的 nAChR 增加上调 Shal K( ) 通道以稳定突触电位。

DOI：
发表时间：
2012-01
期刊：
影响因子：
25
作者：
Ping, Yong;Tsunoda, Susan
通讯作者：
Tsunoda, Susan

Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid-induced Ca2+ hyperexcitation.

逆转 β 淀粉样蛋白诱导的 Ca2 过度兴奋需要选择性烟碱乙酰胆碱受体的共同激活。

DOI：
发表时间：
2019
期刊：
影响因子：
4.2
作者：
Sun, Julianna L;Stokoe, Sarah A;Roberts, Jessica P;Sathler, Matheus F;Nip, Kaila A;Shou, Jiayi;Ko, Kaitlyn;Tsunoda, Susan;Kim, Seonil
通讯作者：
Kim, Seonil

Cell-free reconstitution of multivesicular body (MVB) cargo sorting.

多泡体 (MVB) 货物分选的无细胞重建。