Targeted suppression of mTORC2 reduces seizures across models of epilepsy
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42922-y |
| _version_ | 1797558774497542144 |
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| author | 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 Mauro Costa-Mattioli |
| author_facet | 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 Mauro Costa-Mattioli |
| author_sort | James Okoh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:35:09Z |
| format | Article |
| id | doaj.art-090b16c003544d13bd1df6abfc9cb943 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:35:09Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-090b16c003544d13bd1df6abfc9cb9432023-11-20T09:51:19ZengNature PortfolioNature Communications2041-17232023-11-0114111310.1038/s41467-023-42922-yTargeted suppression of mTORC2 reduces seizures across models of epilepsyJames Okoh0Jacqunae Mays1Alexandre Bacq2Juan A. Oses-Prieto3Stefka Tyanova4Chien-Ju Chen5Khalel Imanbeyev6Marion Doladilhe7Hongyi Zhou8Paymaan Jafar-Nejad9Alma Burlingame10Jeffrey Noebels11Stephanie Baulac12Mauro Costa-Mattioli13Department of Neuroscience, Baylor College of MedicineDepartment of Neuroscience, Baylor College of MedicineInstitut du Cerveau-Paris Brain Institute-ICM, Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié SalpêtrièreDepartments of Chemistry and Pharmaceutical Chemistry, University of California San FransiscoAltos Labs Inc, Bay Area InstituteDepartment of Neuroscience, Baylor College of MedicineDepartment of Neuroscience, Baylor College of MedicineInstitut du Cerveau-Paris Brain Institute-ICM, Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié SalpêtrièreDepartment of Neuroscience, Baylor College of MedicineIonis PharmaceuticalsDepartments of Chemistry and Pharmaceutical Chemistry, University of California San FransiscoDepartment of Neuroscience, Baylor College of MedicineInstitut du Cerveau-Paris Brain Institute-ICM, Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié SalpêtrièreDepartment of Neuroscience, Baylor College of MedicineAbstract 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.https://doi.org/10.1038/s41467-023-42922-y |
| spellingShingle | 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 Mauro Costa-Mattioli Targeted suppression of mTORC2 reduces seizures across models of epilepsy Nature Communications |
| title | Targeted suppression of mTORC2 reduces seizures across models of epilepsy |
| title_full | Targeted suppression of mTORC2 reduces seizures across models of epilepsy |
| title_fullStr | Targeted suppression of mTORC2 reduces seizures across models of epilepsy |
| title_full_unstemmed | Targeted suppression of mTORC2 reduces seizures across models of epilepsy |
| title_short | Targeted suppression of mTORC2 reduces seizures across models of epilepsy |
| title_sort | targeted suppression of mtorc2 reduces seizures across models of epilepsy |
| url | https://doi.org/10.1038/s41467-023-42922-y |
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