MECHANISMS OF BRAIN DYSFUNCTION IN TUBEROUS SCLEROSIS

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 DESCRIPTION (provided by applicant): Tuberous sclerosis complex (TSC) is a genetic disorder, characterized by the formation of tumors in various organs, including the brain. Neurological manifestations, such as epilepsy, intellectual disability, and autism, are typically the most disabling symptoms of TSC. Advances in understanding the molecular pathogenesis of TSC have led to new therapies for tumors in TSC, particularly inhibitors of the mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the pathophysiology of epilepsy and cognitive impairment in TSC is still poorly understood, and treatment of these disabling neurological symptoms remains limited. In previous funding periods of this grant, we utilized mouse models to investigate mechanisms of epileptogenesis in TSC (e.g. Tsc1GFAPCKO mice). We identified a number of cellular and molecular abnormalities in glia and neurons that contribute to epileptogenesis, such as astrocyte proliferation, impaired glial glutamate and potassium buffering, neuronal death, and dysregulation of mTORC1. Most remarkably, we provided evidence that mTORC1 inhibition has antiepileptogenic effects in preventing epilepsy and associated pathological abnormalities in mouse models of TSC, as well as in other models of acquired (non-genetic) epilepsy. In this grant renewal, we propose to extend our previous work by determining more specifically the contribution of non-neuronal cell types and innate immunity in contributing to the neurologic phenotype of TSC. Our general hypothesis is that non-neuronal cells, particularly astrocytes and microglia, play a critical role in the pathophysiology of epilepsy and other neurological manifestations of TSC, by activating inflammatory mechanisms in the brain. This proposal is innovative in focusing on the novel role of non-neuronal cells and innate immunity in the neurological phenotype of TSC. The proposal also has strong clinical significance and impact in testing new mechanistically-targeted therapies, which may benefit the neurological manifestations of not only TSC, but potentially also other neurological disorders.