Slowly inactivating K+ channels in neocortical pyramidal cells

描述(申请人提供)：我们专注于来自躯体感觉皮质的新皮质锥体细胞中电压门控钾通道(Kv)多样性的功能后果。具体地说，我们将研究三种类型的钾通道在新皮质锥体神经元中的功能：Kv1，Kv2和Kv7通道。建议的研究超越了钾通道作为兴奋性的内在刹车的标准概念，研究了这些通道对锥体细胞响应的信息类型的影响，以及这些输入是如何转化为动作电位序列的。将突触输入转换为棘波序列是最基本但也是最重要的神经功能之一。锥体细胞中动作电位的频率和时序对皮层功能都很重要，而且两者都取决于每个神经元的突触输入的强度和时空结构。为了更好地了解特定离子通道的作用，需要在与动物行为相关的条件下进行测试，但目前此类信息非常有限。神经元树突是一种非线性处理器，位于大多数突触和初级棘波产生区之间，但树突的分布式输入对棘波输出的影响在我们对单神经元计算的实验理解中仍然存在巨大差距。我们将使用基于数字光处理(DLP)的系统或双光子显微镜来快速和精确地控制树突状谷氨酸受体激活锥体细胞的时空模式和强度。利用这一模拟的生理输入，我们将研究Kv通道(Kv1、Kv2、Kv7)的影响如何依赖于输入统计数据，以及这些Kv通道如何影响通过放电率对整体输入统计数据的编码(“率编码”)，以及通过精确的尖峰计时(“时间编码”)对单个inPU波动的编码。时间编码对于产生有节奏的皮层活动很重要，例如在注意和感觉处理过程中观察到的。 与公共健康相关：了解特定K通道的详细功能对于了解神经元如何将输入处理为峰值输出以及开发更具体的疾病治疗方法至关重要。K通道功能的改变(如KV1或KV7表达减少)会导致癫痫等病理生理学改变。KV2通道在病理条件下抑制神经元超兴奋性的动态平衡中发挥重要作用，在缺氧条件下介导PC细胞的凋亡，是麻醉药的靶点。

DESCRIPTION (provided by applicant): We focus on the functional consequences of voltage-gated potassium channel (Kv) diversity in neocortical pyramidal cells from somatosensory cortex. Specifically, we will study the functions of three types of potassium channels in neocortical pyramidal neurons: Kv1, Kv2, and Kv7 channels. The proposed studies go beyond the standard notion that potassium channels act as an intrinsic brake on excitability to studying the effects of these channels on the types of information that pyramidal cells respond to and how those inputs are transformed into trains of action potentials. Transformation of synaptic inputs into spike trains is one of the most basic and yet fundamentally important neuronal functions. Both the rate and timing of action potentials in pyramidal cells are important for cortical function, and both depend on the intensity and the spatial and temporal structure of the synaptic input to each neuron. A better understanding of the roles of particular ion channels requires tests under conditions relevant for behaving animals, yet such information is very limited at present. Neuronal dendrites are nonlinear processors, and are interposed between most synapses and the primary spike generating zone, but the effects of distributed input to dendrites on spike output remain a huge gap in our experimental understanding of single-neuron computation. We will use photo uncaging of glutamate with a digital light processing (DLP)-based system or 2-photon microscopy to rapidly and precisely control the spatio-temporal pattern and intensity of dendritic glutamate receptor activation to pyramidal cells. Using this simulated physiological input, we will investigate how the effects of Kv channels (Kv1, Kv2, Kv7) depend on the input statistics and how these Kv channels affect the encoding of overall input statistics by firing rate ("rate coding"), as well as the encoding of individual inpu fluctuations by precise spike timing ("time coding"). Time coding is important for generation of rhythmic cortical activity such as observed during attention and sensory processing. PUBLIC HEALTH RELEVANCE: Knowing the detailed functions of particular K channels is essential to understanding how neurons process inputs into spike outputs and for developing more specific disease therapies. Alterations of K channel function (e.g., reduction of Kv1 or Kv7 expression) leads to pathophysiology such as epilepsy. Kv2 channels play important roles in the homeostatic suppression of neuronal hyperexcitability under pathological conditions, mediate apoptosis in PCs exposed to anoxia, and are targets of anesthetics.