Deconstructing the involvement of abnormally protracted corticogenesis in the etiology of cortical defects in a postnatal mouse model of Tuberous Sclerosis Complex

Among the neurological manifestations associated with Tuberous Sclerosis Complex (TSC), intractable epilepsy associated with cortical tubers (CTs) is one of the major causes of morbidity and deteriorated quality of life in patients. We have recently generated a novel time-specific inducible mutant mouse model of TSC, obtained by deleting Tsc1 and Pten perinatally into subventricular zone (SVZ) progenitors. This model displays several cortical defects, such as disorganized layering and defective interneuron maturation, which are similar to those typically observed in patients’ CTs and resulted in the development of epileptic seizures. In this proposal, we aim at understanding how perinatal SVZ neurogenesis is implicated in the observed cortical anomalies by performing experiments that will allow us to identify the cell types affected by the mutations and to define the gene networks that qualify them. In the long run, the knowledge that we will gain through this project may ultimately lead to the identification of novel pharmacological targets and to the development of disease-modifying treatments beyond mTOR inhibitors.