At the cellular level, loss-of-function mutations in Tsc1 and Tsc2 lead to hyperactivation of mTORC1, which is one of the major mechanisms for TSC pathogenesis (reviewed in Crino, 2013). This mechanism overlaps with other known genetic causes of ASDs. For example, long-term potentiation initiated by BDNF is dependent on mTOR signaling (Tang et al., 2002). Additionally, as the mTOR pathway is involved in protein translation, it is hyperactivated in FXS (Sharma et al., 2010). However, Tsc2+/− mice show reduced protein synthesis, whereas Fmr1−/y mice have increased protein synthesis (Auerbach et al., 2011). One possible explanation for the different effects on protein synthesis is that Rheb has functions other than to negatively regulate mTORC1 activity, which is evident by the fact that inhibition of Rheb, but not inhibition of mTORC1, rescues the aberrant spine morphogenesis observed in Tsc2+/− neurons (Yasuda et al., 2014). More work needs to be done to determine whether ASD-like phenotypes in TSC mouse models are the result from disrupted mTORC1-dependent or mTORC1-independent signaling pathways.
