AUDITORY SIGNALING, THE FUNCTIONAL ROLE OF KV CHANNELS

听觉信号，KV 通道的功能作用

• 批准号: 2908081
• 负责人: BRUCE L TEMPEL
• 金额: $ 28.93万
• 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 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2908081
• 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：(摘自申请者的摘要) 神经生物学面临的一个主要挑战是定义 电压门控性钾(Kv)通道基因影响时间、持续时间和 编码和传递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，明确定义的功能角色(涉及精确的信号保真度) 以及Kv电流的强烈表达。这项提案的目标是审查 Kv通道基因在三种类型听觉中的功能作用 耳蜗核的神经元-丛状神经元和章鱼细胞。和神经细胞 梯形身体的内侧核--每一个都执行相关但不同的任务 信息处理任务。使用分子和免疫细胞化学 技术，申请人将确定Kv通道亚基的补充性 在这些神经元中表达，并检查它们的亚细胞定位。vbl.使用 电生理技术，申请人将表征Kv电流在 野生型小鼠脑干切片和听觉脑片中的听神经元 缺乏Kv1.1通道亚单位基因(即Kv1.1基因敲除)的受损小鼠 老鼠)。这些数据应该揭示管理Kv通道组装和 神经元部分的定位，专用于编码或 信息的传递，并阐明听觉中的特殊作用 对不同的子单元或子单元的子集进行信息处理 亚家族。我们对Kv通道功能作用的全面描述 在细胞水平上也有助于在生物体水平上解释 在Kvl.1基因敲除中观察到听力损失、运动异常和癫痫发作 老鼠。 使用解剖学和电生理学数据，申请者将发展 评估听觉中Kv通道/电流相关性的计算机模型 信息处理。该模型将被用来预测 去除其他在听神经元中强表达的Kv基因，如Kv 1.2 申请人的预测将通过审查直接得到检验 Kvl.2基因敲除小鼠。发作性共济失调肌痉挛是由基因突变引起的 人类的Kvl.1(KCNA1)基因。关于这些患者的临床报告通常包括 耳鸣、眩晕，有时还有严重的听力损失。建议进行的研究及 基于Kvl.1基因敲除小鼠突变体的模型也应该是有信息的 关于这种人类疾病背后的神经元功能障碍。