Hyperactivity of mTORC1 or mTORC2-dependent signaling causes epilepsy downstream of somatic PTEN loss

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, PIC3CA, and AKT, hyperactivate both mTORC1- and mTORC2-dependent signaling. Previous work has 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 LOF in the cortex. Spontaneous seizures and epileptiform activity persisted despite mTORC1 or mTORC2 inactivation alone, but inactivating both mTORC1 and mTORC2 normalized pathology. These results suggest that hyperactivity of both mTORC1 and mTORC2 are sufficient to cause epilepsy, and that targeted therapies should aim to reduce activity of both complexes.