Ion Channel Remodeling in Epilepsy

点击翻译按钮获取中文摘要

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.