Hyperactivity of mTORC1- and mTORC2-dependent signaling mediates epilepsy downstream of somatic PTEN loss

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Gene variants hyperactivating PI3K-mTOR signaling are linked to human epilepsy and cortical malformations.
• While mTORC1 hyperactivity is implicated in mTORpathies, the role of mTORC2 hyperactivity remains unclear.
• Specific gene variants like PTEN, PIK3CA, and AKT can hyperactivate both mTORC1 and mTORC2.

Purpose of the Study:

• To investigate the contribution of mTORC2 hyperactivity to epilepsy and cortical malformations.
• To determine if simultaneous hyperactivation of both mTORC1 and mTORC2 is required for these pathologies.

Main Methods:

• Development of a novel mouse model with somatic Pten loss-of-function (LOF) in the cortex and hippocampus.
• Inactivation of mTORC1 and/or mTORC2 downstream of early Pten deletion.
• Monitoring of brain activity, including spontaneous seizures and epileptiform activity.

Main Results:

• Epilepsy and epileptiform activity persisted upon individual inactivation of either mTORC1 or mTORC2.
• Simultaneous inactivation of both mTORC1 and mTORC2 normalized brain activity in the mouse model.
• These findings indicate that hyperactivity of both complexes contributes to epilepsy.

Conclusions:

• Hyperactivity of both mTORC1 and mTORC2 signaling pathways can independently and collectively contribute to epilepsy.
• Targeted therapies for mTORpathies should aim to inhibit both mTORC1 and mTORC2 complexes.
• This study highlights the dual role of mTORC1 and mTORC2 in neurological disorders.