Ih-Dependent Regulation of Intrinsic Excitability in CA1 Pyramidal Neurons

6.项目摘要 本研究旨在探讨CA 1锥体神经元超极化激活阳离子电流（I{h}）与内源性兴奋性（IE）之间的关系。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I{h}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I{h}介导IE的可塑性的证据都来自使用全细胞电流钳方法对I{h}的间接测量。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I{h}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。

6. Project Summary This proposal is designed to investigate the relationship between the hyperpolarization-activated cation current (I{h}) 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 I{h} 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 I{h}mediated IE comes from indirect measurements of I{h} 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 I{h}) 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.