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.
| Original language | English (US) |
|---|---|
| Article number | 111278 |
| Journal | Cell reports |
| Volume | 40 |
| Issue number | 9 |
| DOIs | |
| State | Published - Aug 30 2022 |
Funding
C.J.Y. receives grant support from NIH 1K08NS107637 , the Hearst Foundation , the Boston Children's Hospital Translational Research Program, and Boston Children’s Office of Faculty Development Career Development Fellowship. This study was supported by the BCH/ Harvard Medical School Intellectual and Developmental Disabilities Research Center (NIH P50HD105351 ), and the BCH Rosamund Stone Zander Translational Neuroscience Center. R.P.C. was supported by a Northwestern University Pulmonary and Critical Care Department Cugell predoctoral fellowship. N.S.C. receives grant support from NIH1R35CA197532 and NIH1PO1AG049665 with metabolomics services provided by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. C.J.Y. receives grant support from NIH 1K08NS107637, the Hearst Foundation, the Boston Children's Hospital Translational Research Program, and Boston Children's Office of Faculty Development Career Development Fellowship. This study was supported by the BCH/Harvard Medical School Intellectual and Developmental Disabilities Research Center (NIH P50HD105351), and the BCH Rosamund Stone Zander Translational Neuroscience Center. R.P.C. was supported by a Northwestern University Pulmonary and Critical Care Department Cugell predoctoral fellowship. N.S.C. receives grant support from NIH1R35CA197532 and NIH1PO1AG049665 with metabolomics services provided by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Conceptualization and methodology, C.J.Y. and M.S; investigation, C.J.Y. J.B.M. S.S. L.R. K.J.G. C.M. D.S.M. and R.P.C.; writing – original draft, C.J.Y.; writing – review & editing, C.J.Y. M.S. and B.D.M.; resources and supervision, N.S.C. B.D.M. and M.S.; funding acquisition, C.J.Y. and M.S. M.S. reports grant support from Novartis, Biogen, Astellas, Aeovian, Bridgebio, and Aucta. He has served on scientific advisory boards for Novartis, Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics, and Alkermes.
Keywords
- CP: Metabolism
- CP: Neuroscience
- GATOR1
- SUDEP
- TSC
- amino acids
- cell signaling
- epilepsy
- fasting
- mTOR
- metabolomics
- seizures
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology