1. Targeted suppression of mTORC2 reduces seizures across models of epilepsy.
- Author
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Okoh, James, Mays, Jacqunae, Bacq, Alexandre, Oses-Prieto, Juan A., Tyanova, Stefka, Chen, Chien-Ju, Imanbeyev, Khalel, Doladilhe, Marion, Zhou, Hongyi, Jafar-Nejad, Paymaan, Burlingame, Alma, Noebels, Jeffrey, Baulac, Stephanie, and Costa-Mattioli, Mauro
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EPILEPSY ,SEIZURES (Medicine) ,NEUROLOGICAL disorders ,GENETIC models ,LABORATORY mice - 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. A loss of neuronal network resilience results in epilepsy. In this study, the authors show that inhibition of mTORC2 suppresses seizures in animal models with multiple aetiologies, thus enhancing neuronal resilience to the pathological hypersynchrony associated with epilepsy. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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