Slowly Inactivating K+ Channels in Neocortical Pyramidal Cells

描述(由申请人提供)：电压门控钾通道控制神经元的兴奋性和神经元活动的造型模式。分子研究已经记录了亚基的多样性，并揭示了一些支配亚基类型关联的规则。对表达系统的研究已经证明了确定的通道类型的生物物理和药理学特性。相比之下，人们对天然膜上钾通道的组成或功能分工知之甚少。我们集中在躯体和树突Kv通道对新皮质锥体细胞将突触输入转换为棘波序列的计算的影响。动作电位的平均速率和时序与新皮质锥体细胞的功能是不可分割的。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起重要作用，并在癫痫皮质中传播癫痫发作。锥体细胞的大部分突触输入是到树突的，因此树突离子通道介于输入和棘波起始点之间。树突状钙依赖的棘波起始区的激活引起的非线性可以导致锥体细胞的内在爆发式放电，这使得突触传递更可靠，并促进了振荡行为。我们以前的工作表明，新皮质锥体细胞表达几个缓慢失活的钾电流。我们将集中研究Kv1和Kv2亚基，描述单通道特性，测试有关通道亚基树突和躯体分布的功能假说，并测试Kv2通道在过滤对噪声输入的反应中的作用(以模拟背景突触输入)。这些数据对于了解锥体细胞如何处理健康和疾病中的突触输入是必不可少的。KV1通道的异常被认为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兴奋性的调节者，也是皮质神经元凋亡的媒介。此外，癫痫发作和缺血改变了Kv2.1通道的分布和性质。与公共健康相关：这些基础研究测试了特定的钾通道亚单位如何影响新皮质锥体细胞进行的树突和体细胞计算，以将输入转换为棘波序列。这些数据对于了解锥体细胞如何处理健康和疾病中的突触输入是必不可少的。

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.