Language
English
Publication Date
11-14-2023
Journal
Nature Communications
DOI
10.1038/s41467-023-42922-y
PMID
37963879
PMCID
PMC10645975
PubMedCentral® Posted Date
11-14-2023
PubMedCentral® Full Text Version
Post-print
Abstract
Epilepsy is a neurological disorder that poses a major threat to public health. Hyperactivation of mTOR complex 1 (mTORC1) is believed to lead to abnormal network rhythmicity associated with epilepsy, and its inhibition is proposed to provide some therapeutic benefit. However, mTOR complex 2 (mTORC2) is also activated in the epileptic brain, and little is known about its role in seizures. Here we discover that genetic deletion of mTORC2 from forebrain neurons is protective against kainic acid-induced behavioral and EEG seizures. Furthermore, inhibition of mTORC2 with a specific antisense oligonucleotide robustly suppresses seizures in several pharmacological and genetic mouse models of epilepsy. Finally, we identify a target of mTORC2, Nav1.2, which has been implicated in epilepsy and neuronal excitability. Our findings, which are generalizable to several models of human seizures, raise the possibility that inhibition of mTORC2 may serve as a broader therapeutic strategy against epilepsy.
Keywords
Mice, Humans, Animals, TOR Serine-Threonine Kinases, Epilepsy, Seizures, Mechanistic Target of Rapamycin Complex 2, Mechanistic Target of Rapamycin Complex 1, Epilepsy, Molecular neuroscience
Published Open-Access
yes
Recommended Citation
Okoh, James; Mays, Jacqunae; Bacq, Alexandre; et al., "Targeted Suppression of mTORC2 Reduces Seizures Across Models of Epilepsy" (2023). Faculty, Staff and Students Publications. 7273.
https://digitalcommons.library.tmc.edu/baylor_docs/7273