This application is for an Independent Scientist Award (K02). The candidate is a pediatric neurologist with a specialty interest in childhood epilepsy, and is currently in the final year of K08 (MCSDA) funding. He recently relocated to the University of California at Irvine (UCI). UCI hosts an internationally recognized basic neuroscience research community, and is well suited to the career development needs of the candidate, especially at this critical time when he has just established an independent laboratory. During the early period of K08 funding, the candidate performed detailed studies of a developmental animal model of epilepsy, the Kv1.1 potassium channel knockout mouse (i.e., the Kcna1-null mutant). Later, the applicant pursued research into the mechanisms underlying the anticonvulsant efficacy of the ketogenic diet (KD), an established but still poorly understood treatment for intractable epilepsy. The KD is a high-fat, low carbohydrate and low-protein diet designed to mimic the early biochemical changes seen upon fasting. The hallmark feature of the KD is the production of the ketone bodies by the liver. The fundamental goal of the proposed studies is to assess the potential role of the GABAergic system in contributing to seizure control by the KD, and in the process establish and validate a clinically relevant animal model of the KD. As a secondary goal, it will be determined whether chronic ketone body exposure can enhance GABAergic inhibition in the brain. Further, the question of whether the KD can exert a lasting antiepileptic effect, beyond the duration of therapy, will be addressed, thereby setting the stage for future studies aimed at determining a mechanistic basis for an anti-epileptogenic effect of the KD. Toward these goals, the effects of the KD on the Kcna1-null mutant will be investigated. In addition, the long-term impact of ketone bodies in hippocampal organotypic slice cultures prepared from these mice will be studied. Neuroanatomical (i.e., histological, immunocytochemical, in situ hybridization) and functional (i.e., video-EEG monitoring, cellular electrophysiological) techniques will be employed in the proposed studies. It is expected that the results of these investigations will shed light on the potential role of the KD in epileptogenesis, especially as it relates to effects on GABAergic inhibition
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