The Impact of Vitamin D on mTOR Signaling, Seizures, and Motor Behavior in a Mouse Model of Hyperactive mTOR Induced Epilepsy and Ataxia

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Project Summary / Abstract Increased mammalian target of rapamycin (mTOR) signaling is a known cause of treatment resistant epilepsy. Pathological mutations to negative regulators of mTOR lead to hyperactive mTOR signaling and have been found in the forebrain and cerebellum of individuals with epilepsy. The cerebellum has recently been shown to contribute to the development of epilepsy. However, research in hyperactive mTOR induced epilepsy has almost exclusively been focused on the hypothalamus and forebrain structures. Individuals that develop seizures associated with hyperactive mTOR in the cerebellum are often resistant to pharmacological intervention and require invasive brain surgery. In severe cases, surgery can fail to control growth and must be repeated. Thus novel treatments are critically needed. Preliminary data show supplemental vitamin D may suppress epilepsy in a mouse model of hyperactive mTOR induced epilepsy and ataxia. This proposal aims to determine whether vitamin D supplementation beginning during adolescence reduces seizures and co- occurring motor impairments (Aim 1A), restores mTOR signaling in adulthood in a rodent model of hyperactive mTOR induced epilepsy and ataxia (Aim 1B) and reverses cerebellar granule cell hypertrophy (Aim 1C). The F99 phase of this fellowship will provide expertise and training in examining the molecular mechanisms underlying genetic causes of neurological disorders and in the testing of novel mechanisms of pharmaceutical therapies. The completion of the F99 phase will provide training that will serve as a springboard for the K00 phase. Baylor University possesses a strong molecular biosciences and imaging core, a dedicated graduate writing center, and faculty and seminars devoted to professional training and teaching. The enclosed proposal for the F99 and K00 phases outlines the training plan for a successful transition from a pre-doctoral trainee to an independent investigator examining treatments for neurodevelopmental disorders.