Tuberous Sclerosis Complex (TSC) is a severe genetic disorder characterized by angiofibroma, mental retardation, and epilepsy, the latter of which likely results from benign malformations known as hamartias and hamartomas. Inactivating mutations in one of two tumor suppressor genes, TSC1 and TSC2, which encode hamartin and tuberin respectively, are thought to underlie the neurological lesions associated with TSC. Although the molecular functions of TSC1 and TSC2 as a negative regulator of the mTOR kinase pathway are well established, there remains considerable confusion as to how TSC gene inactivation results in neurological lesions. The uncertainty of how TSC mutation can result in such gross neurological pathologies stems in part, from the inability to form a viable animal model which faithfully represents the human pathology. Brain lesions in TSC appear to result from a defect in neural progenitor development. For example, hamartias known as cortical tubers are thought to arise during the mid-gestational periods of corticogenesis from radial glia. Tubers can indeed be detected as early as 19 weeks of gestation in humans. In the majority of the cases, tubers affect only a restricted region of the cerebral cortex, suggesting that they form in later rather than earlier periods of cortical development. This proposal seeks to identify a role for TSC1 in radial glia of the perinatal ventricular zone. Biallelic inactivation of a viable TSC1 copy in the presence of an inherited mutant TSC1 during embryonic development will be induced by in utero electroporations. Resulting lesions will be examined to determine the extent to which they recapitulate the human TSC pathology and to identify whether hyper-excitability originates in surrounding tissue, or within the lesion itself.
Tuberous sclerosis complex (TSC) is a multisystem genetic disorder with a preponderance of seizures which are associated with focal cortical lesions known as tubers. TSC is unique in that tubers are readily identified and are often targeted for surgical resection. I propose to develop a novel model of TSC with discreet neurological lesions having features of cortical tubers for which I will measure electrophysiological properties.