RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• Hyperactivation of the mammalian target of rapamycin (mTOR) pathway is linked to malformations of cortical development (MCD), epilepsy, and intellectual disability (ID).
• The precise mechanisms by which mTOR pathway hyperactivity leads to these neurological conditions remain largely unknown.

Purpose of the Study:

• To investigate the underlying mechanisms of epilepsy associated with mTOR pathway hyperactivation.
• To elucidate the role of Ras Homolog Enriched in Brain 1 (RHEB) mutations in cortical development and neuronal function.

Main Methods:

• Utilized a dominant-active mutation in RHEB (RHEBp.P37L) expressed focally in the mouse somatosensory cortex (SScx).
• Analyzed the resulting MCD-like phenotype, including mTOR signaling, neuronal migration, and seizure activity.
• Investigated the contribution of axonal connectivity and vesicle release to seizure generation.

Main Results:

• Focal expression of RHEBp.P37L induced an MCD-like phenotype with increased mTOR signaling, ectopic neurons, and generalized seizures.
• mTOR-dependent seizures were attributed to enhanced axonal connectivity and subsequent hyperexcitability in distally connected neurons.
• Inhibition of axonal vesicle release from RHEBp.P37L neurons abolished seizures and normalized neuronal hyperexcitability.

Conclusions:

• mTOR hyperactivity extends beyond local malformations, causing widespread anatomical and physiological abnormalities.
• Enhanced axonal connectivity driven by mTOR hyperactivity is a key mechanism leading to generalized epilepsy.
• Targeting axonal vesicle release may offer therapeutic strategies for epilepsy linked to mTOR pathway dysregulation.