Epilepsy is one of the most common neurological disorders affecting more than 65 million people worldwide. Although effective anti-epileptic drugs exist, a significant portion of patients (~30%) do not properly respond to currently available drugs. Therefore, there is an urgent need for new strategies to combat such refractory forms of epilepsy. Notably, previous studies have demonstrated that severity of epilepsy is significantly modified by a variety of genetic and environmental factors, raising the exciting future possibility for better management of epilepsy by appropriately manipulating these phenotypic modifiers. The long-term goals of this project are to 1) identify the genetic and environmental modifiers of epilepsy, and elucidate their action mechanisms. New knowledge about such ?epilepsy modifiers? is expected to lead to alternative strategies for prevention and treatment of refractory epilepsy. To attain these goals, the current small project will particularly focus on identification and initial characterization of genetic modifiers for the Drosophila voltage-gated sodium (Nav) channel mutant, Shudderer (Shu) ? a fly model of human epilepsy. In preliminary studies, an unbiased forward genetic screen for modifiers of Shu revealed that severity of the seizure-like phenotypes of Shu is significantly reduced when function of the Glutathione S-transferase S1 (GstS1) gene is suppressed. GstS1 mutations were found to activate antioxidant signaling and increase the levels of the inhibitory neurotransmitter GABA in the Shu brain. Furthermore, it was unexpectedly discovered that a simple dietary modification during development drastically suppresses Shu phenotypes and leads to increased GABA levels in the brain. These intriguing findings has led to the hypothesis that reduced GstS1 function results in suppression of the seizure-like phenotypes of Shu through activation of antioxidant response pathways to modify neural development and enhance GABAergic inhibitory tone in the adult brain. To investigate this hypothesis, this project is designed to collect basic information about genetic modifiers of Shu by pursing the following three specific aims: 1) Determine spatiotemporal requirements of GstS1-dependent modification of Shu's seizure-like phenotypes; 2) Identify additional genetic modifiers of Shu and determine if they affect antioxidant signaling and the GABAergic system. Successful completion of these aims is expected to provide the foundation to understand the role and action mechanisms of genetic modifiers for a fly epilepsy models. Based on evolutionary conservation of the basic neurobiological processes between flies and humans, the outcomes of the proposed experiments will provide fundamental insights into genetic modifiers of human epilepsy, which is expected to lead to the future development of novel strategies for preventing and treating epilepsy that does not respond to conventional therapies. As Shu is a mutant for the evolutionarily conserved Nav channel gene, the future broader impact of this study will be a contribution toward a better understanding of etiology and pathophysiology of other disorders that are linked to abnormal Nav channel functions.
The proposed research will provide new knowledge about genetic factors that influence severity of epilepsy. Such knowledge is relevant to public health and the NIH mission because it is expected to lead to the development of alternative strategies for prevention and treatment of epilepsy that does not respond to currently available drugs.