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

• DOI: 10.1371/journal.pbio.3001279
• Publication Date: 2021-05-26T18:05:08Z
• Authors: Martina Proietti ...; Linda M. C. Koene; Carmen B. Schäfer; Mark Nellist; Marcel de Brito v...; Zhenyu Gao; Ype Elgersma; Geeske M. van Woe...
• Keywords: Neurons; 0301 basic medicine; Epilepsy; QH301-705.5; TOR Serine-Threonine Kinases; Brain; Somatosensory Cortex; Axons; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Seizures; Animals; Ras Homolog Enriched in Brain Protein; Biology (General); Research Article; Signal Transduction

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 inRas 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.