Understanding the Etiology of Tuberous Sclerosis Complex

Abstract

Abstract : Tuberous Sclerosis Complex (TSC) is a genetic multisystem disorder characterized by severe neurological symptoms (e.g., seizures), which are the most significant causes of disability and morbidity. Presently, there are no known cures for TSC and the etiology of the disease is not well understood, perhaps due to the lack of a model system to study the disorder. In TSC patients, mutations in one of two tumor suppressor genes, Tsc1 or Tsc2, result in the formation of lesions. The mechanisms leading to TSC lesions and associated seizure generation during perinatal life remain unclear in the absence of an animal model of TSC lesions. The goal of our recent funding cycle was to generate TSC lesions using a new approach in transgenic Tsc1 mice (Task 1) and to assess at which developmental stages some of the defects start to occur following Tsc1 inactivation (Task 2). We proposed to test the hypothesis that deletion of Tsc genes in perinatal neural progenitor cells contributes to the generation of TSC lesions and subsequent seizures, and to identify the mechanisms underlying that process. To test the hypothesis, we used a double hit model in transgenic mice carrying conditional (fl) and mutant (mut, nonfunctional) Tsc1 alleles (Tsc1(sup fl/mut) mice) by deleting the conditional Tsc1 allele in embryonic and neonatal progenitor cells using in vivo electroporation of Cre recombinase-containing plasmids. We proposed the following two aims: (1) to test whether deletion of Tsc1 in perinatal progenitor cells generates TSC lesions, and to get insights into the mechanisms of tuber formation; and (2) to study the mechanism of cortical hyperexcitability and identify abnormal glutamate receptor expression in Tsc1-null cells. We have accomplished the majority of aim 1. Using a novel technical approach (i.e., in vivo electroporation in mice with conditional and mutant alleles) we generated the first TSC animal model that replicates the discrete cortical lesions seen in humans.