Tuberous sclerosis complex (TSC) is a multiorgan genetic disease in which brain 
involvement causes epilepsy, intellectual disability, and autism. The hallmark 
pathological finding in TSC is the cerebral cortical tuber and its unique 
constituent, giant cells. However, an animal model that replicates giant cells 
has not yet been described. Here, we report that mosaic induction of Tsc1 loss 
in neural progenitor cells in Tsc1(cc) Nestin-rtTA(+) TetOp-cre(+) embryos by 
doxycycline leads to multiple neurological symptoms, including severe epilepsy 
and premature death. Strikingly, Tsc1-null neural progenitor cells develop into 
highly enlarged giant cells with enlarged vacuoles. We found that the vacuolated 
giant cells had multiple signs of organelle dysfunction, including markedly 
increased mitochondria, aberrant lysosomes, and elevated cellular stress. We 
found similar vacuolated giant cells in human tuber specimens. Postnatal 
rapamycin treatment completely reversed these phenotypes and rescued the mutants 
from epilepsy and premature death, despite prenatal onset of Tsc1 loss and mTOR 
complex 1 activation in the developing brain. This TSC brain model provides 
insights into the pathogenesis and organelle dysfunction of giant cells, as well 
as epilepsy control in patients with TSC.