Slowly Inactivating K+ Channels in Neocortical Pyramidal Cells

描述（申请人提供）：电压门控钾通道控制神经元兴奋性和塑造神经元活动模式。分子研究已经记录了亚基的多样性，并揭示了一些控制亚基类型关联的规则。表达系统的研究已经证明了定义的通道类型的生物物理和药理学特性。相比之下，对天然膜中钾通道的组成或功能分工所知相对较少。我们集中研究体细胞和树突Kv通道对新皮质锥体细胞将突触输入转化为尖峰序列的计算的影响。动作电位的平均速率和时间是新皮层锥体细胞功能的组成部分。特别是，锥体细胞的时间选择性促进了皮层回路的节律性和同步性活动，这反过来在体内的注意和知觉过程中很重要，并且是癫痫发作在皮层中扩散的基础。大多数锥体细胞的突触输入都是向树突传递的，因此树突离子通道在输入和尖峰起始位点之间存在。由于树突状Ca2+依赖性尖峰起始区激活引起的非线性可以导致锥体细胞内的突发放电，这使得突触传递更可靠，并促进振荡行为。我们之前的工作表明，新皮质锥体细胞表达几种缓慢失活的钾电流。我们将专注于Kv1和Kv2亚基，描述单通道特性，测试关于通道亚基树突与体细胞分布的功能假设，并测试Kv2通道在过滤噪声输入响应（模拟背景突触输入）中的作用。这些数据对于理解锥体细胞如何处理健康和疾病中的突触输入至关重要。Kv1通道异常与癫痫和共济失调有关。Kv2通道是麻醉剂的靶点，是许多神经元和非神经元细胞类型的兴奋性调节剂，也是皮质神经元凋亡的介质。此外，Kv2.1通道的分布和性质会因癫痫发作和缺血而改变。公共卫生相关性：这些基础研究测试了特定钾通道亚基如何影响新皮层锥体细胞进行的树突和体细胞计算，将输入转化为尖峰序列。这些数据对于理解锥体细胞如何处理健康和疾病中的突触输入至关重要。

DESCRIPTION (provided by applicant): Voltage-gated potassium channels control neuronal excitability and sculpt patterns of neuronal activity. Molecular studies have documented the diversity of subunits and revealed some of the rules governing the association of subunit types. Studies in expression systems have demonstrated the biophysical and pharmacological properties of defined channel types. In contrast, relatively little is known about the composition or functional division of labor of potassium channels in native membranes. We concentrate on the influence of somatic and dendritic Kv channels on computations made by neocortical pyramidal cells to convert synaptic inputs into spike trains. The average rate and timing of action potentials are integral to the functions of neocortical pyramidal cells. In particular, temporal selectivity of pyramidal cells facilitates rhythmic and synchronous activity in cortical circuits, which in turn is important in attentional and perceptual processes in vivo and underlies spread of seizures in epileptic cortex. Most synaptic inputs to pyramidal cells are to dendrites, thus dendritic ion channels are interposed between inputs and the site of spike initiation. Nonlinearities due to activation of a dendritic Ca2+dependent spike initiation zone can lead to intrinsic burst firing in pyramidal cells, which makes synaptic transmission more reliable and facilitates oscillatory behavior. Our previous work indicates that neocortical pyramidal cells express several slowly-inactivating potassium currents. We will concentrate on Kv1 and Kv2 subunits and characterize single channel properties, test functional hypotheses concerning dendritic vs. somatic distribution of channel subunits, and test for a role of Kv2 channels in filtering responses to noisy inputs (to mimic background synaptic inputs). These data are essential for understanding how pyramidal cells process synaptic inputs in health and disease. Abnormalities of Kv1 channels have been implicated in epilepsy and ataxia. Kv2 channels are targets of anesthetic agents, regulators of excitability in many neuronal and nonneuronal cell types, and mediators of apoptosis in cortical neurons. In addition, the distribution and properties of Kv2.1 channels are altered by seizures and ischemia. PUBLIC HEALTH RELEVANCE: These basic studies test how specific potassium channel subunits influence dendritic and somatic computations made by neocortical pyramidal cells to convert inputs into spike trains. These data are essential for understanding how pyramidal cells process synaptic inputs in health and disease.