Modulation of h-channels in hippocampal dendrities

描述(由申请人提供)：癫痫是一种神经元兴奋性异常的疾病，但这种过度兴奋性的原因在很大程度上仍不清楚。近年来，由于技术的进步，我们对神经元兴奋性的内在决定因素的理解有了显著的提高，这使得对神经元树突的电生理研究成为可能，例如CA1海马区和新皮质锥体神经元的树突。这项建议调查了颞叶癫痫与电压门控通道的生物物理特性改变有关的可能性，电压门控通道主要局限于树突、h通道或ih。先前的研究发现，海马锥体神经元中的Ih可以被一次长时间的癫痫发作所改变，Ih是抗惊厥作用的靶点。我们建议研究海马锥体神经元树突中的Ih，以确定其特性在慢性癫痫动物模型中是否发生改变。由于PI和其他人之前的工作表明，树突Ih降低了整个锥体神经元的兴奋性，我们的中心假设是Ih可能在癫痫动物的锥体神经元树突中下调，产生神经元的超兴奋性。这些研究涉及用脑片技术制备的CA1区锥体神经元胞体和树突的全细胞和细胞附着性膜片钳电生理学。具体地说，我们将回答以下问题：1)在正常情况下，锥体神经元树突中Ih是如何调节的？2)癫痫动物的锥体神经元树突中Ih的性质是否发生了变化？3)在慢性癫痫中，树突Ih是否存在差异调节？这些研究可能会为癫痫的部分原因是神经元内在兴奋性的改变这一假说提供进一步的证据，并可能提出新的靶点，如h通道或其调节剂，用于癫痫的治疗。PI最近在华盛顿大学开设了一个致力于细胞神经生理学的实验室，并将癫痫成年人作为当地癫痫中心的一部分进行治疗。如果得到资助，这项建议将使PI能够转变为一名独立的临床医生兼科学家，在职业生涯中专注于癫痫的基础和临床方面。

DESCRIPTION (provided by applicant): Epilepsy is a disease of abnormal neuronal excitability, but the causes of this hyperexcitability remain largely unknown. Our understanding of the intrinsic determinants of neuronal excitability has significantly improved in recent years due to technical advances which allow electrophysiological study of neuronal dendrites, such as those of CA1 hippocampal and neocortical pyramidal neurons. This proposal investigates the possibility that temporal lobe epilepsy is associated with altered biophysical properties of a voltage-gated channel, which is primarily localized to dendrites, the h-channel or Ih. Prior studies have found that Ih in hippocampal pyramidal neurons can be altered by a single prolonged seizure, and that Ih is a target of anticonvulsant action. We propose studying Ih in hippocampal pyramidal neuron dendrites to determine if its properties are altered in an animal model of chronic epilepsy. Because prior work by the PI and others has shown that dendritic Ih reduces overall pyramidal neuron excitability, our central hypothesis will be that Ih may be down-regulated in the dendrites of pyramidal neurons in epileptic animals, producing neuronal hyperexcitability. The studies proposed involve whole-cell and cell-attached patch clamp electrophysiology in the soma and dendrites of CA1 hippocampal pyramidal neurons prepared using brain slice techniques. Specifically, we will answer the following questions: 1) How is Ih modulated under normal conditions in pyramidal neuron dendrites? 2) Are Ih properties altered in pyramidal neuron dendrites from epileptic animals? 3) Is dendritic Ih differentially modulated in chronic epilepsy? These studies may provide further evidence for the hypothesis that epilepsy results in part from changes in the intrinsic excitability of neurons, and may suggest novel targets, such as the h-channel or its modulators, in the treatment of epilepsy. The PI has recently started a laboratory at the University of Washington devoted to cellular neurophysiology, and treats adults with epilepsy as part of the Regional Epilepsy Center there. If funded, this proposal will enable the PI's transition to an independent clinician-scientist with a career focus on both basic and clinical aspects of epilepsy.