Expression and Function of K+ Channel Genes in Brain

该项目的长期目标是帮助理解K+通道多样性在中枢神经系统(CNS)中的作用。K+通道调节神经元的兴奋性。它们构成了特定神经元在功能特性上的许多差异，导致了神经元信息编码和整合的复杂性。据推测，它们的多样性为神经元回路和神经递质的活动提供了信号特异性。编码K+通道的基因突变已被发现会导致癫痫、精神分裂症和自闭症。这一建议侧重于皮质GABA能抑制中间神经元的一种亚型，称为快峰(FS)细胞，以其以非常高的频率激发持续动作电位(AP)的能力而命名。GABA能中间神经元是大脑皮层的重要组成部分，在信息处理、可塑性、皮层节律的产生和癫痫的发病机制中具有重要作用。了解负责FS细胞功能的分子元件对于控制皮质功能、了解生理和生理状况以及为治疗药物提供靶点是至关重要的。最近发现，定位于FS细胞轴突起始段(AIS)的KV1亚家族的K+通道动态调节其活性。这一更新应用的目的是验证这样的假设，即存在于FS神经元AIS的具有特定特性的KV1通道控制着FS细胞在大脑皮层中介导的抑制的时间。实验将表征AIS的KV1通道的分子组成和组织，以及它们对新皮质神经元AP生成的不同调节(目标1)。实验还将研究KV1通道在FS细胞对生物相关刺激反应的放电行为中的作用(目标2)，以及KV1通道在FS神经元的皮质节律活动和感觉处理中的作用(目标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).