The Auditory Phenotype of Kv Channel Gene Mutations

描述（由申请人提供）：拟议工作的长期目标是了解中枢听觉系统神经元的内在电兴奋性如何有助于听觉信号处理。细胞膜中表达的电压门控钾（Kv）通道的类型和量决定了动作电位的形状、概率和时间模式，因此主要决定了神经元的内在电兴奋性。Kv通道的生物化学和生物物理学的详细分析表明，两个Kv通道，Kv3.1和Kv1.3，表现出的属性，特别是密切相关的目标，这一建议。已经观察到Kv1.3和Kv3.1在调节神经元反应阈值、最大持续放电率和最大跟随率方面具有显著的且通常相反的作用。这些响应特征的改变对声学信号处理有明确的影响，这将通过在Kv3.1和Kv1.3敲除小鼠中结合使用神经生理学和行为测定来深入探讨。目的1旨在描述Kv3.1和Kv1.3缺失在下丘（IC）内单个单位水平的影响。将在清醒的Kv3.1 null、Kv1.3 null和野生型小鼠中比较声音频率、时间包络特性、强度和双耳相互作用的变化的神经生理学选择性。目标2将神经生理反应的变化与听力阈值的相应变化联系起来。这些实验将实施条件回避协议，以测量检测和辨别阈值的声音频率，时间结构和强度的变化。通过遗传学、神经生理学和行为学分析的结合应用，拟议的实验将进一步加深我们对大脑兴奋性的基本组成部分如何影响听觉处理和感知的理解。 相关性：这些实验将进一步加深我们对大脑功能和行为的分子决定因素的理解。通过研究单基因缺失对大脑单细胞生理反应特性和积极参与听力任务的动物听力的影响，拟议的实验可能使我们能够在听觉系统功能的更综合背景下构建基因突变的影响。此外，所提出的实验可以进一步阐明内在神经元兴奋性在听觉信息处理以及病理状态（如听源性癫痫发作）中的作用。

DESCRIPTION (provided by applicant): The long-term objective of the proposed work is to understand how the intrinsic electrical excitability of neurons in central auditory system contributes to auditory signal processing. The type and amount of voltage- gated potassium (Kv) channels expressed in the cell membrane determine the shape, probability and temporal patterning of action potentials and therefore principally determine a neuron's intrinsic electrical excitability. Detailed analyses of Kv channel biochemistry and biophysics indicate that two Kv channels, Kv3.1 and Kv1.3, exhibit properties that are particularly germane to the aims of this proposal. Kv1.3 and Kv3.1 have been observed to have significant - and often opposing - roles in regulating the neuronal response threshold, maximum sustained firing rate and maximum following rate. Alterations in these response features have clear implications for acoustic signal processing, which will be explored in depth through the combined use of neurophysiological and behavioral assays in Kv3.1 and Kv1.3 knockout mice. Aim 1 seeks to characterize the effects of Kv3.1 and Kv1.3 deletion at the level of the single unit within the inferior colliculus (IC). Neurophysiological selectivity for variations in sound frequency, temporal envelope properties, intensity and binaural interaction will be compared in awake Kv3.1 null, Kv1.3 null and wild-type mice. Aim 2 would relate variations in neurophysiological responses to commensurate shifts in hearing thresholds. These experiments will implement a conditioned avoidance protocol to measure detection and discrimination thresholds for variations in sound frequency, temporal structure and intensity. Through the combined application of genetic, neurophysiological and behavioral analyses, the proposed experiments would further our understanding of how the basic building blocks of excitability in the brain impact auditory processing and perception. Relevance: These experiments will further our understanding of the molecular determinants of brain function and behavior. By studying the effects of single gene deletions on the physiological response properties of single cells in the brain and the hearing abilities of animals actively engaged in listening tasks, the proposed experiments may allow us to frame the effects of genetic mutations in a more integrative context of auditory system function. Furthermore, the proposed experiments could shed additional light on the role of intrinsic neuronal excitability in the context of auditory information processing as well as pathological states such as audiogenic seizure.