Role of Kv3 Potassium Channels in Arousal-State Dynamics

描述（由申请人提供）：电压门控钾（Kv）通道形成了一个大而多样的离子通道家族，参与调节静息膜电位、动作电位波形、神经递质释放和神经元的节律性放电模式。它们的关键作用在由Kv通道基因突变引起的几种遗传性人类疾病中得到了强调。在许多不同类型的Kv通道中，Kv 3型通道显示出独特的生物物理特性：非常快速的激活和失活动力学，高激活阈值和大单位电导，使神经元能够以极高频率激发窄动作电位的特性。Kv3.1和Kv3.3通道的亚基在已知参与调节睡眠-觉醒周期和运动活动的几个脑区域中表达。当这些基因中的一个或两个的功能被遗传消除时，突变小鼠显示Kv 3无效等位基因依赖性变化，包括由于不稳定的慢波睡眠和组成性多动而导致的严重睡眠丧失。为了了解位于不同脑区的神经元亚群的电特性改变如何导致观察到的行为改变，我们建议选择性抑制WT小鼠神经元亚群中的Kv 3活性。将使用编码显性负性Kv3.1通道亚基的重组腺相关病毒实现Kv 3活性的细胞特异性消融。脑区域特异性抑制Kv 3活动，结合脑切片记录和行为测试，将使我们能够将不同神经元亚群中改变的神经元放电模式与相应改变的睡眠-觉醒行为联系起来。因此，Kv 3突变小鼠将作为明确定义的模型来研究多动和睡眠功能障碍的病理生理学。我们已经开发了钾通道突变小鼠，作为定义明确的啮齿动物模型，以研究特定脑区的电生理变化，这些脑区由于睡眠不稳定而导致组成性多动和功能失调的睡眠-觉醒模式。

DESCRIPTION (provided by applicant): Voltage-gated potassium (Kv) channels form a large and diverse family of ion channels that are involved in regulating the resting membrane potential, the action potential waveform, neurotransmitter release and rhythmic firing patterns of neurons. Their pivotal role is highlighted by several inherited human diseases caused by mutations in Kv channel genes. Among the many different types of Kv channels, Kv3-type channels display unique biophysical properties: very rapid activation and deactivation kinetics, high thresholds of activation and large unit conductances, properties that enable neurons to fire narrow actions potentials at extremely high frequencies. Subunits for Kv3.1 and Kv3.3 channels are expressed in several brain regions known to be involved in the regulation the sleep-wake cycle and of motor activity. When the function of one or both of these genes is genetically eliminated, mutant mice display Kv3-null allele-dependent changes that include severe sleep loss, due to unstable slow-wave sleep, and constitutive hyperactivity. To understand how the altered electrical properties of neuronal subpopulations located in distinct brain areas cause the observed behavioral alterations, we propose to selectively suppress Kv3 activity in subsets of neurons in WT mice. Cell-specific ablation of Kv3 activity will be achieved using recombinant adeno-associated virus encoding a dominant-negative Kv3.1 channel subunit. Brain region-specific suppression of Kv3 activity in combination with brain-slice recordings and behavioral tests will enable us to correlate altered neuronal firing patterns in distinct neuronal subpopulations with the correspondingly altered sleep-wake behavior. Hence, Kv3 mutant mice will serve as well-defined models to study the pathophysiology of hyperactivity and sleep dysfunction. We have developed potassium channel-mutant mice that serve as well-defined rodent models to study the electrophysiological changes in particular brain regions that cause constitutive hyperactivity and dysfunctional sleep-wake patterns due to unstable sleep.