DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting
Christopher J. Yuskaitis, Jinita B. Modasia, Sandra Schrötter, Leigh‐Ana Rossitto, Karenna J. Groff, Christopher Morici, Divakar S. Mithal, Ram Prosad Chakrabarty, Navdeep S. Chandel, Brendan D. Manning, Mustafa Şahin
Abstract
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.