Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease that 
prominently features brain malformations (tubers) with many patients suffering 
from epilepsy and autism. These malformations typically exhibit neuronal as well 
as glial cell abnormalities and likely underlie much of the neurological 
morbidity seen in TSC. Tuber pathogenesis remains poorly understood though 
upregulation of the mTORC1 signaling pathway in TSC has been consistently 
demonstrated. Here we address abnormal brain development in TSC by inactivating 
the mouse Tsc1 gene in embryonic neural progenitor cells. This strategy permits 
evaluation of the role of the Tsc1 gene in both neuronal as well as glial cell 
lineages. Tsc1(Emx1-Cre) conditional knockout (CKO) animals die by 25 days of 
life. Their brains have increased size and contain prominent large cells within 
the cerebral cortex that have greatly increased mTORC1 signaling and decreased 
mTORC2 signaling. Severe defects of cortical lamination, enlarged dysmorphic 
astrocytes and decreased myelination were also found. Tsc1(Emx1-Cre) CKO mice 
were then treated with rapamycin to see if the premature death and brain 
abnormalities can be rescued. Postnatal rapamycin treatment completely prevented 
premature death and largely reversed the glia pathology but not abnormal 
neuronal lamination. These findings support a model that loss of function of the 
TSC genes in embryonic neural progenitor cells causes cortical malformations in 
patients with TSC. The dramatic effect of rapamycin suggests that even with 
extensive multi-lineage abnormalities, a postnatal therapeutic window may exist 
for patients with TSC.