AUDITORY SIGNALING, THE FUNCTIONAL ROLE OF KV CHANNELS

听觉信号，KV 通道的功能作用

• 批准号: 6618084
• 负责人: BRUCE L TEMPEL
• 金额: $ 31.37万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6618084
• 关键词: action potentials; auditory nuclei; auditory pathways; brain stem; computer simulation; electron microscopy; electrophysiology; gene mutation; gene targeting; hearing disorders; immunocytochemistry; laboratory mouse; neural conduction; neural information processing; potassium channel; voltage gated channel

DESCRIPTION:(from applicant's summary) A major challenge confronting neurobiology is to define how specific voltage-gated potassium (Kv) channel genes influence the timing, duration and frequency of the neuronal signals that encode and transmit information. Neurons in the auditory system have the unique advantages of relatively simple circuitry, well defined functional roles (involving precise signal fidelity) and strong expression of Kv currents. The goal of this proposal is to examine the functional roles of Kv channel genes in three types of auditory neuron-bushy neurons and octopus cells of the cochlear nucleus. and neurons of the medial nucleus of the trapezoid body -each performing related but distinct information processing tasks. Using molecular and irnmunocytochemical techniques, the applicant will determine the complement of Kv channel subunits expressed in these neurons and examine their subcellular localizations. Using electrophysiological techniques, the applicant will characterize Kv currents in these auditory neurons in brainstem slices from wildtype mice and from hearing impaired mice that lack the Kv1.1 channel subunit gene (i.e. Kvl.l knockout mice). These data should reveal rules governing Kv channel assembly and localization in parts of the neuron specialized for either encoding or transmission of information, and elucidate specialized roles in auditory information processing for different subunits, or subsets of subunits within a subfamily. Our thorough characterization of the functional role of Kv channels at the cellular level will also help to explain at the organismal level the hearing loss, movement abnormalities and seizures observed in Kvl.1 knockout mice. Using both anatomical and electrophysiological data, the applicant will develop computer models to assess the relevance of Kv channels/currents in auditory information processing. The model will be used to predict the effects of removing other Kv genes strongly expressed in auditory neurons, such as Kv 1.2 for which the applicant's predictions will be tested directly by examining Kvl.2 knockout mice. Episodic ataxia myokymia is caused by mutations in the Kvl.1 (KCNA1) gene in humans. Clinical reports on these patients often include tinnitus, vertigo and sometimes profound hearing loss. The proposed studies and models based on the Kvl.1 knockout mouse mutants should also be informative regarding the neuronal dysfunction that underlies this human disease.

描述：（从申请人的摘要） 神经生物学面临的主要挑战是定义如何具体 电压门控钾（KV）通道基因影响时间，持续时间和 编码和传输信息的神经元信号的频率。神经元 在听觉系统中，有相对简单的独特优势 电路，定义明确的功能角色（涉及精确的信号保真度） KV电流的强烈表达。该提议的目的是检查 KV通道基因在三种类型的听觉中的功能作用 耳蜗核的神经元浸泡神经元和章鱼细胞。和神经元 梯形体的内侧核与表演相关但不同 信息处理任务。使用分子和irnmunocytotoalical 技术，申请人将确定KV通道亚基的补充 在这些神经元中表达并检查它们的亚细胞局部化。使用 电生理技术，申请人将表征KV电流 来自野生型小鼠的脑干切片中的这些听觉神经元和听力 缺乏KV1.1通道亚基基因的小鼠（即kvl.l敲除） 小鼠）。这些数据应揭示有关KV通道组件的规则，并且 在神经元的部分地区定位，专门用于编码或 信息传输，并阐明听觉中的专业角色 针对不同亚基的信息处理，或一个子集的子集 亚家族。我们对KV通道功能作用的透彻表征 在细胞水平上，还将有助于解释有机体水平 听力损失，运动异常和在KVL中观察到的癫痫发作。1敲除 老鼠。 使用解剖学和电生理数据，申请人将发展 计算机模型评估听觉中KV频道/电流的相关性 信息处理。该模型将用于预测 去除在听觉神经元中强烈表达的其他KV基因，例如KV 1.2 申请人的预测将通过检查直接测试 KVL.2淘汰小鼠。情节性共济失调肌症是由突变引起的 人类中的KVL.1（KCNA1）基因。这些患者的临床报告通常包括 耳鸣，眩晕，有时是深远的听力损失。拟议的研究和 基于KVL的模型。1基因敲除小鼠突变体也应提供信息 关于这种人类疾病的神经元功能障碍。