Ih-Dependent Regulation of Intrinsic Excitability in CA1 Pyramidal Neurons

描述(由申请人提供)： 本研究旨在探讨CA1区锥体神经元超极化激活阳离子电流(Ih)与固有兴奋性(IE)之间的关系。先前的研究分别证明了长时抑制(LTD)和长时程增强(LTP)诱导后IE的增强或减弱，一些生理学研究表明iH是IE可塑性的最有可能的中介(Fan等人，2005；Brager和Johnston，2007；Narayanan和Johnston，2007)。然而，所有描述Ih介导的IE可塑性的证据都来自于使用全细胞电流钳方法间接测量Ih。因此，这种现象背后的机制仍然不清楚，这代表着我们对IE在这些神经元中的调控的理解存在很大差距。这项建议直接研究IE可塑性的生物物理机制，使用能够确定单个H-通道(负责Ih的离子通道)的生物物理性质的电压钳方法作为主要工具。具体地说，将调查LTP后IE的减少和LTP后IE的增加。这项工作将对我们理解IE在CA1锥体神经元中的动态平衡做出实质性的贡献。 公共卫生相关性： 最近的几份报告表明，在CA1区锥体神经元中，颞叶癫痫(TLE)和脑出血之间存在联系(Shin等人，2008年；Jung等人，2007年)。在这些神经元中，IH作为一种活性依赖的内在兴奋性(IE)调节因子发挥作用，而与TLE相关的观察到的病理生理学可能源于IH介导的IE内稳态的失败。这一建议旨在直接研究目前尚不清楚的iH介导的IE内稳态的生物物理机制，并有助于阐明与TLE相关的获得性iH-通道病的病理生理学。

DESCRIPTION (provided by applicant): This proposal is designed to investigate the relationship between the hyperpolarization-activated cation current (Ih) and intrinsic excitability (IE) of CA1 pyramidal neurons. Previous work demonstrated enhanced or reduced IE following the induction of long-term depression (LTD) and long-term potentiation (LTP), respectively, and several physiological studies have implicated Ih as the most likely mediator of IE plasticity (Fan et al., 2005; Brager and Johnston, 2007; Narayanan and Johnston, 2007). However, all evidence describing the plasticity of Ihmediated IE comes from indirect measurements of Ih using the whole cell current-clamp method. The mechanism underlying this phenomenon therefore remains unclear, and represents a substantial gap in our understanding of the regulation of IE in these neurons. This proposal investigates the biophysical mechanism of IE plasticity directly, using voltage-clamp methods capable of determining the biophysical properties of single h-channels (the ion channels responsible for Ih) as the primary tool. Specifically, the reduction in IE following LTP and the increase in IE following LTD will be investigated. This work will represent a substantial contribution to our understanding of IE homeostasis in CA1 pyramidal neurons. PUBLIC HEALTH RELEVANCE: Several recent reports have demonstrated a link between temporal lobe epilepsy (TLE) and Ih in CA1 pyramidal neurons (Shin et al., 2008; Jung et al., 2007). Ih functions as an activity-dependent regulator of intrinsic excitability (IE) in these neurons, and the observed pathophysiology associated with TLE likely stems from a failure of Ih-mediated IE homeostasis. This proposal is designed to directly investigate the currently unknown biophysical mechanism for Ih-mediated IE homeostasis, and will help to shed light on the pathophysiology of the acquired Ih-channelopathy associated with TLE.