Slowly inactivating K+ channels in neocortical pyramidal cells

描述（由申请人提供）：我们关注的是来自体感觉皮层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。具体来说，我们将研究三种钾通道在新皮质锥体神经元中的功能：Kv1， Kv2和Kv7通道。拟议的研究超越了钾通道作为兴奋性的内在制动器的标准概念，研究这些通道对锥体细胞响应的信息类型的影响，以及这些输入如何转化为动作电位序列。将突触输入转化为脉冲序列是最基本也是最重要的神经元功能之一。锥体细胞中动作电位的速率和时间对皮质功能都很重要，并且都取决于每个神经元的突触输入的强度和空间和时间结构。为了更好地了解特定离子通道的作用，需要在与行为动物相关的条件下进行测试，但目前这类信息非常有限。神经元树突是非线性处理器，位于大多数突触和初级尖峰产生区之间，但树突的分布式输入对尖峰输出的影响在我们对单神经元计算的实验理解中仍然是一个巨大的空白。我们将利用基于数字光处理（DLP）的系统或双光子显微镜对谷氨酸进行光捕获，以快速准确地控制树突状谷氨酸受体对锥体细胞激活的时空模式和强度。利用这种模拟的生理输入，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通道如何通过发射率（“率编码”）影响总体输入统计数据的编码，以及通过精确的尖峰时序（“时间编码”）影响单个输入波动的编码。时间编码对于有节奏的皮层活动的产生是重要的，例如在注意和感觉处理过程中观察到的。

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.