TSC2-mTORC1 axis regulates morphogenesis and neurological function of Gli1+ adult-born dentate granule cells.

Aberrant adult hippocampal neurogenesis is implicated in neurological and mood disorders associated with dysregulation of the mechanistic target of rapamycin (mTOR). Understanding how the mTOR pathway shapes the functional development of different subpopulations of adult-born hippocampal neural stem cells will enable insight into potential therapeutic pathways for these disorders. Here we study how loss of TSC2, a regulator of mTOR pathway and a causal gene for tuberous sclerosis complex (TSC), affects dentate gyrus granule cell morphogenesis and hippocampal-dependent function. We found that Tsc2^KO mice with TSC2 specifically ablated from Gli1⁺ adult-born neural stem cells showed neuronal hypertrophy, reduced NEUN expression, increased dendritic arborization, premature cellular senescence, and hypervascularization of the dentate gyrus. Neurologically, Tsc2^KO mice showed altered exploratory behavior, impaired spatial learning, abnormal contextual recall, and hypersensitivity to kainic acid-induced seizures. Importantly, genetic reduction of Raptor, essential for mTORC1 signaling, rebalanced mTORC1 signaling and mitigated molecular, cellular, and neurological deficits in Tsc2^KO mice. This study uncovered functions of TSC2 in Gli1⁺ adult-born neural stem cells and highlights RAPTOR as a potential therapeutic target for reversing disease features associated with TSC2 mutations.