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

PLoS Biol. 2021 May 26;19(5):e3001279. doi: 10.1371/journal.pbio.3001279. eCollection 2021 May.


Hyperactivation of the mammalian target of rapamycin (mTOR) pathway can cause malformation of cortical development (MCD) with associated epilepsy and intellectual disability (ID) through a yet unknown mechanism. Here, we made use of the recently identified dominant-active mutation in Ras Homolog Enriched in Brain 1 (RHEB), RHEBp.P37L, to gain insight in the mechanism underlying the epilepsy caused by hyperactivation of the mTOR pathway. Focal expression of RHEBp.P37L in mouse somatosensory cortex (SScx) results in an MCD-like phenotype, with increased mTOR signaling, ectopic localization of neurons, and reliable generalized seizures. We show that in this model, the mTOR-dependent seizures are caused by enhanced axonal connectivity, causing hyperexcitability of distally connected neurons. Indeed, blocking axonal vesicle release from the RHEBp.P37L neurons alone completely stopped the seizures and normalized the hyperexcitability of the distally connected neurons. These results provide new evidence of the extent of anatomical and physiological abnormalities caused by mTOR hyperactivity, beyond local malformations, which can lead to generalized epilepsy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Brain / metabolism
  • Disease Models, Animal
  • Epilepsy / metabolism
  • Epilepsy / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism
  • Ras Homolog Enriched in Brain Protein / metabolism*
  • Seizures / metabolism*
  • Seizures / physiopathology
  • Signal Transduction
  • Somatosensory Cortex / metabolism
  • TOR Serine-Threonine Kinases / metabolism*


  • Ras Homolog Enriched in Brain Protein
  • Rheb protein, mouse
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases

Grants and funding

This work was supported by the Dutch TSC foundation (STSN) (G.M.v.W) and the Dutch Epilepsy foundation (Epilepsie fonds) (Y.E.). GMvW was supported by the Dutch Research Counsil (NWO) Vidi Grant (016.Vidi.188.014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.