| Autor: |
Cullen ER; Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington VT, 05405, USA., Safari M; Fralin Biomedical Research Institute at VTC, Center for Neurobiology Research, Roanoke VA, 24016, USA., Mittelstadt I; Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington VT, 05405, USA., Weston MC; Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington VT, 05405, USA.; Fralin Biomedical Research Institute at VTC, Center for Neurobiology Research, Roanoke VA, 24016, USA.; School of Neuroscience, Virginia Polytechnic and State University, Blacksburg VA, 24060, USA. |
| Abstrakt: |
Gene variants that hyperactivate PI3K-mTOR signaling in the brain lead to epilepsy and cortical malformations in humans. Some gene variants associated with these pathologies only hyperactivate mTORC1, but others, such as PTEN , PIK3CA , and AKT , hyperactivate both mTORC1- and mTORC2-dependent signaling. Previous work established a key role for mTORC1 hyperactivity in mTORopathies, however, whether mTORC2 hyperactivity contributes is not clear. To test this, we inactivated mTORC1 and/or mTORC2 downstream of early Pten deletion in a new model of somatic Pten loss-of-function (LOF) in the cortex and hippocampus. Spontaneous seizures and epileptiform activity persisted despite mTORC1 or mTORC2 inactivation alone, but inactivating both mTORC1 and mTORC2 simultaneously normalized brain activity. These results suggest that hyperactivity of both mTORC1 and mTORC2 can cause epilepsy, and that targeted therapies should aim to reduce activity of both complexes. |
