Ion Channel Remodeling in Epilepsy
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:
- to evaluate whether there are alterations in Kv4.2 channel expression and localization in hippocampus during status epilepticus;
- to investigate whether alterations in the half-life and trafficking of Kv4.2 is a candidate mechanism for these changes and whether post-translational mechanisms contribute to this effect; and
- to evaluate whether Kv4.2 deficiency contributes to increased seizure susceptibility and whether overexpression of Kv4.2 blocks this effect. We will use a combination of biochemical, molecular, and electrophysiology techniques to evaluate Kv4.2 expression and mechanisms of regulation following convulsant stimulation in vivo and in vitro models.
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.
Relevance of the project to IDDRC mission:
Kv4.2 ion channels are involved in synaptic plasticity. Learning and memory deficits occur in animal lacking this channel. Furthermore, this channel has been linked to epilepsy. The aim of this project is to study the expression and mechanisms of regulation following convulsant stimulation in immature and mature animals and to understand the developmental regulation of this channel.