Tuberous sclerosis complex (TSC) is a genetic disease with severe neurologic and 
psychiatric manifestations including epilepsy, developmental delay, and autism. 
Despite much progress in defining abnormal signaling pathways including the 
contribution of increased mTORC1 signaling, specific abnormalities that underlie 
the severe neurologic features in TSC remain poorly understood. We hypothesized 
that epilepsy and autism in TSC result from abnormalities of γ-aminobutyric 
acidergic (GABAergic) interneurons. To test this hypothesis, we generated 
conditional knockout mice with selective deletion of the Tsc1 gene in GABAergic 
interneuron progenitor cells. These interneuron-specific Tsc1 conditional 
knockout (CKO) mice have impaired growth and decreased survival. Cortical and 
hippocampal GABAergic interneurons of CKO mice are enlarged and show increased 
mTORC1 signaling. Total numbers of GABAergic cells are reduced in the cortex 
with differential reduction of specific GABAergic subtypes. Ectopic clusters of 
cells with increased mTORC1 signaling are also seen suggesting impaired 
interneuron migration. The functional consequences of these cellular changes are 
evident in the decreased seizure threshold on exposure to the proconvulsant 
flurothyl. These findings support an important role for the Tsc1 gene during 
GABAergic interneuron development, function, and possibly migration.