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

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Scientist Development Award - Research (K02)
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NST-2 Subcommittee (NST)
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Fureman, Brandy E
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St. Joseph's Hospital and Medical Center
United States
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Simeone, Timothy A; Simeone, Kristina A; Samson, Kaeli K et al. (2013) Loss of the Kv1.1 potassium channel promotes pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices. Neurobiol Dis 54:68-81
Kim, Do Young; Vallejo, Johana; Rho, Jong M (2010) Ketones prevent synaptic dysfunction induced by mitochondrial respiratory complex inhibitors. J Neurochem 114:130-41
Maalouf, Marwan; Rho, Jong M; Mattson, Mark P (2009) The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev 59:293-315
Davis, Laurie M; Pauly, James R; Readnower, Ryan D et al. (2008) Fasting is neuroprotective following traumatic brain injury. J Neurosci Res 86:1812-22
Kim, Do Young; Fenoglio, Kristina A; Simeone, Timothy A et al. (2008) GABAA receptor-mediated activation of L-type calcium channels induces neuronal excitation in surgically resected human hypothalamic hamartomas. Epilepsia 49:861-71
Maalouf, Marwan; Rho, Jong M (2008) Oxidative impairment of hippocampal long-term potentiation involves activation of protein phosphatase 2A and is prevented by ketone bodies. J Neurosci Res 86:3322-30
Kim, Do Young; Rho, Jong M (2008) The ketogenic diet and epilepsy. Curr Opin Clin Nutr Metab Care 11:113-20
Maalouf, M; Sullivan, P G; Davis, L et al. (2007) Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience 145:256-64
Kim, Do Young; Davis, Laurie M; Sullivan, Patrick G et al. (2007) Ketone bodies are protective against oxidative stress in neocortical neurons. J Neurochem 101:1316-26
Fenoglio, Kristina A; Wu, Jie; Kim, Do Young et al. (2007) Hypothalamic hamartoma: basic mechanisms of intrinsic epileptogenesis. Semin Pediatr Neurol 14:51-9

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