Ion Channel Remodeling in Epilepsy

描述（由申请人提供）：长期持续的癫痫发作活动（癫痫持续状态）与显著的死亡率和发病率相关。这里概述的研究重点是了解癫痫持续状态中涉及的细胞机制。我们推测，离子通道调节的活性依赖性改变有助于增加网络兴奋性，并可能增强癫痫持续状态。在这项提案中，我们将集中在了解一个特定的离子通道，Kv4.2在癫痫持续状态的调节机制。Kv4.2通道是海马中突触后兴奋性的关键调节剂，海马是大脑的癫痫倾向区域。这些通道定位于海马神经元的树突，在那里它们是瞬时A型K+电流的主要贡献者。在神经元接受突触输入的这个区域中，Kv4.2通道的电压依赖性激活提供了调节突触后兴奋性的关键机制。翻译后修饰参与Kv4.2通道的调节。最近，我们已经确定了癫痫持续状态后海马Kv4.2通道的异常调节，其净总和预计会导致树突中A型K+电流的减少，从而增加突触后兴奋性。在这些研究中，我们将评估参与惊厥刺激后突触后膜Kv4.2通道重塑的候选机制。该提案的目的是：1）评估癫痫持续状态期间海马中Kv4.2通道表达和定位是否存在改变; 2）研究Kv4.2半衰期和运输的改变是否是这些变化的候选机制; 3）评估翻译后机制是否有助于这种效应。我们将使用生物化学，分子，成像和生理学技术的组合，以评估Kv4.2的表达和调节机制，在体内和体外模型惊厥刺激后。我们希望这些研究的结果将为癫痫持续状态期间Kv4.2的调节机制提供新的见解，这些研究将为癫痫持续状态治疗的新干预措施的开发提供见解。公共卫生相关性：长期、持续的癫痫发作活动（癫痫持续状态）与显著的死亡率和发病率相关。这里概述的研究重点是了解癫痫持续状态期间离子通道活性依赖性改变的机制。我们假设这些机制有助于增加网络兴奋性和潜在的癫痫持续状态的增强。我们希望这些研究的结果将为癫痫持续状态治疗的新干预措施的发展提供见解。

DESCRIPTION (provided by applicant): Prolonged, continuous seizure activity (status epilepticus) is associated with significant mortality and morbidity. The studies outlined here focus on understanding the cellular mechanisms that are involved in status epilepticus. We hypothesize that activity-dependent alterations in ion channel regulation contribute to increased network excitability and possibly the potentiation of status epilepticus. In this proposal we will focus on understanding the mechanisms underlying the regulation of a particular ion channel, Kv4.2 during status epilepticus. Kv4.2 channels are critical regulators of postsynaptic excitability in the hippocampus, which is a seizure prone region of the brain. These channels are localized to the dendrites of hippocampal neurons where they are major contributors to the transient A-type K+ current. In this region where the neurons receive synaptic input, the voltage-dependent activation of Kv4.2 channels provides a critical mechanism for regulating postsynaptic excitability. Post-translational modifications are involved in the regulation of Kv4.2 channels. Recently, we have identified aberrant regulation of Kv4.2 channels in hippocampus acutely following status epilepticus, the net sum of which is predicted to lead to decreases in the A-type K+ current in the dendrites and thereby increase postsynaptic excitability. In these studies, we will evaluate candidate mechanisms involved in the remodeling of Kv4.2 channels in the postsynaptic membrane following convulsant stimulation. The aims of the proposal are: 1) to evaluate whether there are alterations in Kv4.2 channel expression and localization in hippocampus during status epilepticus; 2) to investigate whether alterations in the half-life and trafficking of Kv4.2 is a candidate mechanism for these changes and 3) to evaluate whether post-translational mechanisms contribute to this effect. We will use a combination of biochemical, molecular, imaging, and physiology techniques to evaluate Kv4.2 expression and mechanisms of regulation following convulsant stimulation in models in vivo and in vitro. Our hope is that the findings from these studies will provide novel insights into the mechanisms involved in the regulation of Kv4.2 during status epilepticus and that these studies will provide insights into the development of new interventions for the treatment of status epilepticus. PUBLIC HEALTH RELEVANCE: Prolonged, continuous seizure activity (status epilepticus) is associated with significant mortality and morbidity. The studies outlined here focus on understanding the mechanisms that are involved in activity-dependent alterations in ion channels during status epilepticus. We hypothesize that these mechanisms contribute to increased network excitability and potentially the potentiation of status epilepticus. Our hope is that the findings from these studies will provide insights into the development of new interventions for the treatment of status epilepticus.