Chronic Intermittent Ethanol and Kv4.2 Channels

慢性间歇性乙醇和 Kv4.2 通道

• 批准号: 8888766
• 负责人: L Judson Chandler
• 金额: $ 33.64万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888766
• 关键词: Action Potentials; Acute; Adult; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Apical; Back; Biochemical; Biochemistry; Brain; C-terminal; Chronic; Cognition; Cognitive deficits; Coupled; Coupling; Data; Dendrites; Dendritic Spines; Development; Distal; Down-Regulation; Electrophysiology (science); Ethanol; FDA approved; Functional disorder; Glutamates; Hippocampus (Brain); Impaired cognition; Impairment; Knowledge; Kv4.2 channel; Learning; Measures; Mediating; Memory impairment; Messenger RNA; Modeling; Molecular Target; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; Performance; Pharmacotherapy; Potassium; Potassium Channel; Preparation; Proteins; Rattus; Relapse; Reporting; Role; Signal Transduction; Slice; Surface; Synapses; Synaptic plasticity; System; Technology; Testing; Time; Translations; Treatment outcome; Up-Regulation; Viral Vector; Work; alcohol exposure; alcohol related problem; alcohol use disorder; chronic alcohol ingestion; cognitive function; cognitive task; design; effective therapy; glutamatergic signaling; hippocampal pyramidal neuron; in vivo; multi-electrode arrays; neuroadaptation; neuromechanism; neurotransmission; new therapeutic target; novel; optogenetics; prevent; problem drinker; protein transport; public health relevance; receptor expression; research study; response; signal processing; therapeutic target; voltage

 DESCRIPTION (provided by applicant): Heavy alcohol consumption is associated with hippocampal dysfunction. Evidence suggests that hippocampal-dependent cognitive impairments in alcoholics are a contributing factor in high relapse rates and poor treatment outcomes. Chronic alcohol exposure remodels glutamatergic synapses, and these structural and functional neuroadaptations have been implicated in learning and memory deficits. However, there is a substantial gap in our knowledge about the neural mechanisms that underlie alcohol-associated cognitive decline. In CA1 pyramidal neurons of the hippocampus, voltage-dependent potassium (Kv) channels comprised of Kv4.2 a subunits are enriched in distal dendrites and underlie the subthreshold transient A-type K+ current (ISA). Kv4.2 channels function to critically regulate neuronal signaling by modulating synaptic integration and plasticit. Previous work has shown that surface expression of Kv4.2 is promoted through interaction with a group of proteins called K+ channel interacting proteins (KChIPs). Emerging evidence suggests that there is a functional coupling between Kv4.2 channels and NMDA receptors that may be critical for plasticity and is regulated by KChIP3. Our preliminary data demonstrate that chronic ethanol treatment of organotypic hippocampal slice cultures reduces Kv4.2 channel function and surface expression and enhances Ca2+ transients evoked by back-propagating action potentials (bAPs) in distal apical dendrites of CA1 pyramidal neurons. In addition, chronic ethanol significantly reduced KChIP3 expression and increased NMDA receptor expression. In adult rats, chronic intermittent ethanol (CIE) exposure down-regulates Kv4.2 channel expression and impairs performance on hippocampal-dependent tasks. Thus, our preliminary data have identified Kv4.2 channels and KChIP3 as promising molecular targets that underlie aberrant signal processing in CA1 pyramidal neurons in following chronic alcohol exposure. We have designed a comprehensive yet focused set of studies to test the overarching hypothesis of this proposal that the reduction in Kv4.2 channel function and up-regulation of NMDA receptors by chronic ethanol exposure contributes to enhanced bAP signaling, aberrant plasticity and hippocampal dysfunction. The proposed studies involve a multifaceted approach that involves biochemistry, slice electrophysiology, multielectrode recording, optogenetics, and viral vector technologies to test the following hypotheses: Aim 1) Test the hypothesis that CIE bidirectionally alters expression of Kv4.2 channels and NMDA receptors in the hippocampus through modulation of KChIP3; Aim 2) Test the hypothesis that CIE reduces expression and function of Kv4.2 channels and alters spike timing- dependent synaptic plasticity in the acute slice preparation; and Aim 3) Determine whether CIE alters the cognitive function of the hippocampus and induces aberrant hippocampal plasticity in vivo. These studies will advance our knowledge of the neural mechanisms contributing to ethanol-associated impairments in synaptic plasticity and cognitive function and identify novel therapeutic targets for more effective treatment of alcoholism and alcohol-related problems.

 描述（由适用提供）：大量饮酒与海马功能障碍有关。有证据表明，酗酒者海马依赖性认知障碍是高继电器率和不良治疗结果的促成因素。慢性酒精暴露重塑了谷氨酸能突触，并且在学习和记忆中暗示了这些结构和功能性神经适应。但是，我们对与酒精相关的认知能力下降的神经力学的知识存在很大的差距。在海马的CA1锥体神经元中，由Kv4.2组成的电压依赖性钾（KV）通道富含不同的树突，并构成亚阈值瞬变瞬变A-Type K+电流（ISA）。 Kv4.2通道功能通过调节合成整合和塑性来严格调节神经元信号传导。先前的工作表明，Kv4.2的表面表达是通过与一组称为K+通道相互作用蛋白（Kchips）的蛋白质相互作用来促进的。新兴的证据表明，KV4.2通道和NMDA接收器之间存在功能耦合，这可能对可塑性至关重要，并且受KCHIP3的调节。我们的初步数据表明，有机海马切片培养物的慢性乙醇治疗可降低KV4.2通道功能和表面表达，并增强CA1倍增神经元的盘状动作电位（BAP）引起的Ca2+瞬变。另外，慢性乙醇显着降低了KCHIP3表达和NMDA受体表达增加。在成年大鼠中，慢性间歇性乙醇（CIE）暴露降低了KV4.2通道表达，并损害海马依赖性任务的性能。因此，我们的初步数据已将KV4.2通道和KCHIP3鉴定为在慢性酒精暴露后CA1锥体神经元中异常信号加工基础的分子靶标。我们设计了一系列全面但重点的研究集，以检验该提案的总体假设，即通过慢性乙醇暴露对KV4.2通道功能的降低和NMDA受体的上调有助于增强BAP信号传导，异常的可塑性和HippocAmpal功能障碍。拟议的研究涉及一种多方面的方法，涉及生物化学，切片电生理学，多电极记录，光遗传学和病毒载体技术来检验以下假设：目标1）测试CIE双向在Kv4.2 Channel和NMDA受体中的表达来测试kv4.2 Channels and NMDA受体的表达。目标2）测试CIE降低Kv4.2通道的表达和功能的假设，并改变了急性切片制剂中尖峰时序依赖性突触可塑性；目标3）确定CIE是否会改变海马的认知功能，并在体内诱导异常海马可塑性。这些研究将提高我们对有助于乙醇相关的突触可塑性和认知功能损害的神经机制的了解，并确定新的治疗靶标，以更有效地治疗酒精中毒和与酒精有关的问题。