RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity.
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 Enr...
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Online Access: | https://doi.org/10.1371/journal.pbio.3001279 |
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doaj-8d4f132af9724879a8c6978f1a5986182021-06-21T04:30:53ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852021-05-01195e300127910.1371/journal.pbio.3001279RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity.Martina Proietti OnoriLinda M C KoeneCarmen B SchäferMark NellistMarcel de Brito van VelzeZhenyu GaoYpe ElgersmaGeeske M van WoerdenHyperactivation 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.https://doi.org/10.1371/journal.pbio.3001279 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Martina Proietti Onori Linda M C Koene Carmen B Schäfer Mark Nellist Marcel de Brito van Velze Zhenyu Gao Ype Elgersma Geeske M van Woerden |
spellingShingle |
Martina Proietti Onori Linda M C Koene Carmen B Schäfer Mark Nellist Marcel de Brito van Velze Zhenyu Gao Ype Elgersma Geeske M van Woerden RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity. PLoS Biology |
author_facet |
Martina Proietti Onori Linda M C Koene Carmen B Schäfer Mark Nellist Marcel de Brito van Velze Zhenyu Gao Ype Elgersma Geeske M van Woerden |
author_sort |
Martina Proietti Onori |
title |
RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity. |
title_short |
RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity. |
title_full |
RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity. |
title_fullStr |
RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity. |
title_full_unstemmed |
RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity. |
title_sort |
rheb/mtor hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2021-05-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.pbio.3001279 |
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