Effects of dietary alpha-linolenic acid on SUDEP, seizures, and neural structure and function in mouse models of epilepsy

项目总结

PROJECT SUMMARY Currently available medications fail to control seizures in ~30% of epilepsy patients. This is a serious medical problem because patients with severe progressive forms of drug-resistant epilepsy have a high risk of sudden unexpected death in epilepsy (SUDEP). Thus, the need for novel and effective strategies for the prevention and treatment of epilepsy is pressing. Among the potential adjunctive therapies for such refractory forms of epilepsy, diet-based approaches hold great promise as they are often economical and associated with few ad- verse side effects. Our long-term goal is to provide the scientific foundation necessary for developing new effective interventions for combating drug-resistant epilepsy. To this end, it will be necessary to elucidate the molecular and cellular mechanisms through which dietary modifications reduce seizures and SUDEP. The overall objectives of this exploratory project are to determine 1) the beneficial effects of dietary supplementation with -linolenic acid (ALA), an essential -3 polyunsaturated fatty acid (PUFA), on mouse models of epilepsy, and 2) how “therapeutic diets” affect the morphology and physiological function of brain neurons that are relevant to epilepsy. Our central hypothesis is that orally administered ALA and milk whey reduce phenotypic severity in mouse models of epilepsy by inducing morphological and physiological changes in brain GABAergic neurons. This hypothesis is based, in part, on our preliminary findings in fruit flies and mice: 1) supplementation of diets with milk whey significantly suppresses neuronal and behavioral hyperexcitability in Drosophila, as well as spontaneous seizures and SUDEP in epileptic mice, and 2) ALA in milk whey mediates this diet-induced suppression of seizures in Drosophila. The current project will use mouse voltage-gated sodium channel mutants, well-established models of human epilepsy. Aim #1 is to determine the effects of ALA on SUDEP and seizures. Mice that model Dravet syndrome (Scn1aR1407X/+) and early infantile epileptic encephalopathy (Scn8aN1768D/+) will be fed ALA daily after weaning, and spontaneous seizures and SUDEP will be monitored under continuous video surveillance. Hyperthermia-induced seizures will also be scored for frequency and severity in the presence or absence of ALA feeding. Aim #2 is to delineate diet- induced morphological and physiological alterations in brain neurons. The effects of milk whey and ALA on the morphology of neocortical GABAergic interneurons will be assessed by examining their numbers, dendritic complexity, axonal projections, and terminal density in Scn1aR1407X/+ mutants. The effects of therapeutic diets on the function of GABAergic neurons will also be determined, by patch clamp recordings from neocortical slices. The proposed research is significant because it is expected to identify the beneficial effects of dietary modifications on mouse models of genetic epilepsy under well-controlled conditions, as well as the changes in brain neurons that are induced by diet. These outcomes represent a solid foundation for future studies of the molecular and cellular mechanisms by which modified diets protect against epilepsy.