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CA 1锥体神经元超极化激活阳离子电流（Ih）与内源性兴奋性（IE）的关系。先前的工作证明了分别在诱导长时程抑制（LTD）和长时程增强（LTP）后增强或减少IE，并且几项生理学研究已经暗示Ih是IE可塑性的最可能的介质（Fan等人，2005; Brager和约翰斯顿，2007; Narayanan和约翰斯顿，2007）。然而，所有描述Ih介导的IE的可塑性的证据都来自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不清楚，并代表了我们在这些神经元中的IE调节的理解的一个重大差距。该建议直接研究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）的生物物理特性的电压钳方法作为主要工具。具体而言，将研究LTP后IE的减少和LTD后IE的增加。这项工作将代表一个实质性的贡献，我们了解IE稳态CA 1锥体神经元。 公共卫生相关性： 最近的几个报道已经证明了颞叶癫痫（TLE）和CA 1锥体神经元中的Ih之间的联系（Shin等人，2008; Jung等人，2007年）。Ih在这些神经元中作为内在兴奋性（IE）的活性依赖性调节剂发挥作用，并且观察到的与TLE相关的病理生理学可能源于Ih介导的IE稳态的失败。该建议旨在直接研究Ih介导的IE稳态的目前未知的生物物理机制，并将有助于阐明与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.