Mechanisms of Brain Dysfunction in Tuberous Sclerosis

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DESCRIPTION (provided by applicant): Neurological complications, such as epilepsy, mental retardation, and autism, represent common sources of significant morbidity and mortality in children with tuberous sclerosis complex (TSC). Epilepsy, in particular, can be especially devastating and is often refractory to available treatments. Understanding the molecular, biochemical, and physiological mechanisms underlying epileptogenesis in TSC is critical to the development of more effective therapies for seizures in patients with TSC. Seizures and other neurological symptoms of TSC reflect the presence of characteristic developmental brain abnormalities, such as cortical tubers. Cortical tubers contain abnormally differentiated neuroglial cells and excessive gliosis, suggesting that glial cells may be important in the pathophysiology of epilepsy and brain dysfunction in TSC. To understand the contribution of glial cells to TSC brain dysfunction, we developed a novel mouse model of TSC (Tsc1[GFAP]CKO mice), in which Tsd inactivation in glia results in abnormalities in glial growth, proliferation, and differentation, neuronal disorganization, and severe epilepsy. The primary goal of this proposal is to elucidate the molecular, biochemical, and electrophysiological mechanisms by which glial defects in Tsd lead to seizures in Tsc1[GFAP]CKO mice. We hypothesize that glial Tsd inactivation results in impaired uptake of glutamate and potassium by astrocytes, which may promote epileptogenesis by causing abnormal extracellular glutamate and potassium homeostasis, excitotoxic neuronal death, and hyperexcitable neuronal circuits. In this project, we propose to determine the effects of glial Tsd inactivation on 1) the expression and function of specific astrocyte glutamate transporters and potassium channels, 2) extracellular glutamate and potassium levels, 3) induction of excitotoxic neuronal death, and 4) neuronal excitability on both the single cell and circuit levels in Tsc1[GFAP]CKO mice. Furthermore, the involvement of specific cellular signaling pathways, previously implicated in TSC, in mediating these effects will be investigated. In these studies, we will employ a unique combination of molecular genetic, biochemical, and electrophysiological approaches in the context of a successful, synergistic collaboration between two independent research laboratories to address these critical issues. In addition to defining the cellular and molecular mechanisms causing seizures specifically in TSC, these studies should provide broader insights into the general role of glial cells in epileptogenesis and identify novel therapies for seizures directed at astrocytes that may benefit all patients with epilepsy. Since epilepsy affects approximately 1% of all people, this research has the potential to have significant impact on public health.