Modulation of h-channels in hippocampal dendrities

描述（由申请人提供）：癫痫是一种异常神经元兴奋性的疾病，但这种过度兴奋性的原因在很大程度上仍然未知。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（如CA1海马和新皮质锥体神经元）的电生理研究成为可能。本研究探讨了颞叶癫痫与电压门控通道生物物理特性改变有关的可能性，该通道主要定位于树突，即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，并且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，以确定其性质是否在慢性癫痫动物模型中发生改变。由于PI和其他人之前的工作已经表明，树突Ih降低了锥体神经元的整体兴奋性，我们的中心假设将是癫痫动物锥体神经元树突中的Ih可能下调，从而产生神经元的高兴奋性。采用脑切片技术对CA1海马锥体神经元的体细胞和树突进行全细胞和细胞贴附膜片钳电生理研究。具体来说，我们将回答以下问题：1)正常情况下锥体神经元树突中的Ih是如何调节的？2)癫痫动物锥体神经元树突的Ih特性是否发生改变？树突状Ih在慢性癫痫中是否有差异调节？这些研究可能为癫痫部分由神经元内在兴奋性变化引起的假设提供进一步的证据，并可能在癫痫治疗中提出新的靶点，如h通道或其调节剂。PI最近在华盛顿大学开设了一个实验室，专门研究细胞神经生理学，并作为区域癫痫中心的一部分治疗成人癫痫患者。如果获得资助，该提案将使PI转变为一个独立的临床科学家，其职业重点是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.