Expression and Function of K+ Channel Genes in Brain

该项目的长期目标是有助于了解K+通道多样性在中枢神经系统（CNS）中的作用。K+通道调节神经元兴奋性。它们构成了表征特定神经元的许多功能特性差异的基础，有助于神经元信息编码和整合的复杂性。据推测，它们的多样性提供了信号特异性的神经元电路和神经递质的行动。已发现编码K+通道的基因突变会导致癫痫、精神分裂症和自闭症。该建议的重点是皮质GABA能抑制性中间神经元的一种亚型，称为快速尖峰（FS）细胞，因其能够以非常高的频率发射持续的动作电位（AP）序列而命名。GABA能中间神经元是大脑皮层的关键组成部分，在信息处理、可塑性、皮层节律的产生和癫痫发作的发病机制中具有重要作用。负责FS细胞功能的分子元素的知识是至关重要的操纵皮质功能，以了解生理和病理生理条件，并提供治疗药物的目标。最近发现，Kv1亚家族的K+通道，特异性地定位于FS细胞的轴突起始段（AIS），动态地调节其活性。本更新申请的目的是检验以下假设：存在于FS神经元AIS处的具有特定性质的Kv1通道控制皮质中FS细胞介导的抑制的时间。实验将表征AIS处Kv1通道的分子组成和组织及其对新皮层神经元之间AP产生的差异调节（Aim 1）。实验还将研究Kv1通道在FS细胞响应生物相关刺激的放电行为中的作用（目的2），以及Kv1通道在FS神经元皮质节律活动和感觉处理中的作用（目的3）。

The long term goal of this project is to contribute to the understanding of the role of K+ channel diversity in the central nervous system (CNS). K+ channels regulate neuronal excitability. They underlie many of the differences in functional properties that characterize specific neurons, contributing to the complexity of neuronal information coding and integration. It is hypothesized that their diversity provides signaling specificity to neuronal circuits and to the actions of neurotransmitters. Mutations in genes encoding K+ channels have been found to cause epilepsy, schizophrenia and autism. This proposal focuses on a subtype of cortical GABAergic inhibitory interneuron known as the fast-spiking (FS) cell, named for its ability to fire sustained trains of action potentials (APs) at remarkably high frequencies. GABAergic interneurons are key components of the cerebral cortex and have essential roles in information processing, plasticity, the generation of cortical rhythms, and in the pathogenesis of seizures. Knowledge of the molecular elements responsible for FS cell function is critical for the manipulation of cortical function to understand physiological and patophysiological conditions and to provide targets for therapeutic drugs. It was recently discovered that K+ channels of the Kv1 subfamily, specifically localized to the axon initial segment (AIS) of FS cells dynamically regulate their activity. The goal of this renewal application is to test the hypothesis that Kv1 channels with specific properties, present at the AIS of FS neurons, control the timing of FS cell-mediated inhibition in the cortex. Experiments will characterize the molecular composition and organization of Kv1 channels at the AIS and their differential regulation of AP generation among neocortical neurons (Aim 1). Experiments will also investigate the role of Kv1 channels in the firing behavior of FS cells in response to biologically relevant stimuli (Aim 2) and the role of Kv1 channels in FS neurons in cortical rhythmic activity and sensory processing (Aim 3).