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Targeted suppression of mTORC2 reduces seizures across models of epilepsy

Author

Listed:
  • James Okoh

    (Baylor College of Medicine
    Baylor College of Medicine
    Altos Labs Inc, Bay Area Institute)

  • Jacqunae Mays

    (Baylor College of Medicine
    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
    Baylor College of Medicine
    Novartis Inc)

  • Khalel Imanbeyev

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Marion Doladilhe

    (Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière)

  • Hongyi Zhou

    (Baylor College of Medicine
    Baylor College of Medicine
    Altos Labs Inc, Bay Area Institute)

  • Paymaan Jafar-Nejad

    (Ionis Pharmaceuticals)

  • Alma Burlingame

    (University of California San Fransisco)

  • Jeffrey Noebels

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Stephanie Baulac

    (Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière)

  • Mauro Costa-Mattioli

    (Baylor College of Medicine
    Baylor College of Medicine
    Altos Labs Inc, Bay Area Institute)

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.

Suggested Citation

  • 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, 2023. "Targeted suppression of mTORC2 reduces seizures across models of epilepsy," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42922-y
    DOI: 10.1038/s41467-023-42922-y
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    References listed on IDEAS

    as
    1. Esther Krook-Magnuson & Caren Armstrong & Mikko Oijala & Ivan Soltesz, 2013. "On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy," Nature Communications, Nature, vol. 4(1), pages 1-8, June.
    2. Vasiliki Karalis & Franklin Caval-Holme & Helen S. Bateup, 2022. "Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Tomi Suomi & Fatemeh Seyednasrollah & Maria K Jaakkola & Thomas Faux & Laura L Elo, 2017. "ROTS: An R package for reproducibility-optimized statistical testing," PLOS Computational Biology, Public Library of Science, vol. 13(5), pages 1-10, May.
    4. Yehezkel Sztainberg & Hong-mei Chen & John W. Swann & Shuang Hao & Bin Tang & Zhenyu Wu & Jianrong Tang & Ying-Wooi Wan & Zhandong Liu & Frank Rigo & Huda Y. Zoghbi, 2015. "Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides," Nature, Nature, vol. 528(7580), pages 123-126, December.
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