Targeted suppression of mTORC2 reduces seizures across models of epilepsy

James Okoh, Jacqunae Mays, Alexandre Bacq, Juan A. Oses-Prieto, Stefka Tyanova, Chien-Ju Chen, Khalel Imanbeyev, Marion Doladilhe, Hongyi Zhou, Paymaan Jafar-Nejad, Alma Burlingame, Jeffrey Noebels, Stephanie Baulac and Mauro Costa-Mattioli ()
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James Okoh: Baylor College of Medicine
Jacqunae Mays: Baylor College of Medicine
Alexandre Bacq: Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière
Juan A. Oses-Prieto: University of California San Fransisco
Stefka Tyanova: Altos Labs Inc, Bay Area Institute
Chien-Ju Chen: Baylor College of Medicine
Khalel Imanbeyev: Baylor College of Medicine
Marion Doladilhe: Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière
Hongyi Zhou: Baylor College of Medicine
Paymaan Jafar-Nejad: Ionis Pharmaceuticals
Alma Burlingame: University of California San Fransisco
Jeffrey Noebels: Baylor College of Medicine
Stephanie Baulac: Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière
Mauro Costa-Mattioli: Baylor College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42922-y

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