DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting

Caloric restriction and acute fasting are known to reduce seizures but through unclear mechanisms. mTOR signaling has been suggested as a potential mechanism for seizure protection from fasting. We demonstrate that brain mTORC1 signaling is reduced after acute fasting of mice and that neuronal mTORC1 integrates GATOR1 complex-mediated amino acid and tuberous sclerosis complex (TSC)-mediated growth factor signaling. Neuronal mTORC1 is most sensitive to withdrawal of leucine, arginine, and glutamine, which are dependent on DEPDC5, a component of the GATOR1 complex. Metabolomic analysis reveals that Depdc5 neuronal-specific knockout mice are resistant to sensing significant fluctuations in brain amino acid levels after fasting. Depdc5 neuronal-specific knockout mice are resistant to the protective effects of fasting on seizures or seizure-induced death. These results establish that acute fasting reduces seizure susceptibility in a DEPDC5-dependent manner. Modulation of nutrients upstream of GATOR1 and mTORC1 could offer a rational therapeutic strategy for epilepsy treatment. [Display omitted] •mTORC1 integrates amino acid and growth factor signaling in neurons•Knockdown of DEPDC5 and/or TSC2 leads to sustained mTORC1 signaling with fasting•Neuronal DEPDC5 loss reduces serotonin levels and provokes seizure-induced death•Acute fasting protects from seizures by DEPDC5-mediated amino acid sensing mechanisms Yuskaitis et al. find that amino acid sensing through GATOR1 and mTORC1 mediates the protective effects of dietary fasting on seizures. Through their thorough investigation of the upstream regulation of neuronal mTORC1 signaling, they provide insight into nutrient-signaling mechanisms in the brain and how these mechanisms mediate seizures.