Perturbation of overall activity of mTOR pathway in mouse model of focal cortical dysplasia

Abstract

Focal cortical dysplasia (FCD) is neurodevelopmental disorder associated with drug-resistant epilepsy. Histopathological spectrum of FCD is broad, including cortical dyslamination in the absence or presence of significant cellular defects, FCD Type I and Type II respectively. Somatic mutations in mTOR pathway genes such as MTOR, TSC1 and TSC2 have been found in FCD type II however, a clear genotype-phenotype correlation has not been established to explain FCD type I. In this study, we found that the severity of developmental defects is associated with the overall activity of the mTOR pathway. In developing mouse brain, ectopic overexpression of gain-of-function mutations in the components of upstream mTOR pathway caused cortical dyslamination and cellular defects seen in FCD type II, whereas expression of wildtypes caused cortical dyslamination only. We now aim to characterize transcriptional profiles to reveal the molecular mechanisms underlying phenotypic differences caused by the perturbation of overall activity of mTOR pathway.