Epilepsy is a common neurological disorder. Basic research in the field of epilepsy has focused on understanding the cellular and molecular mechanisms that underlie the disorder. The goal of this proposal is to evaluate the role that the mitogen-activated protein kinase (MAPK) signaling cascade plays in epilepsy. We have shown that MAPK regulates K channel activity and synaptic plasticity. Furthermore MAPK activation leads to long-lasting changes in the hippocampus through regulation of gene transcription. Recent studies have demonstrated MAPK activation in animal models of epilepsy, although the downstream targets of MAPK in epilepsy are unknown. We propose that the MAPK cascade plays a critical role in the genesis of the acute and chronic phases of epilepsy through regulation of K channel activity and gene transcription. Regulation of K channel activity could impact membrane excitability, and recent studies have shown that humans and genetic mouse models with K channel mutations have an epilepsy phenotype. MAPK regulation of transcription factors such as cyclic AMP response element binding protein (CREB) could contribute to the chronic changes seen in epilepsy (i.e. hippocampal sclerosis). Our preliminary results show hippocampal MAPK activation, an increase in NLAPK phosphorylation of a dendritic K channel subunit, Kv4.2, and increases in CREB phosphorylation in the kainate model of epilepsy. To further support a role for the MAPK cascade in epilepsy we have pilot studies showing that inhibition of the MAPK cascade blocks the expression of kainate-induced limbic motor seizures. In this proposal we wish to test the hypotheses that: 1) the MAPK cascade is activated in hippocampus following kainate-induced status epilepticus and is necessary for kainate-induced epileptogenesis; 2) the K channel subunit, Kv4.2, is an effector of MAPK in the kainate model of epilepsy; and 3) the transcription factor, CREB, is an effector of MAPK in the kainate model of epilepsy. By further defining the role of the MAPK signaling cascade in epilepsy we hope to gain insight into the basic mechanisms contributing to this disorder. Thus these studies may lead to the development of new treatments for epilepsy.
