In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 5 ( 2021-5-26), p. e3001279-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001279
DOI:
10.1371/journal.pbio.3001279.g001
DOI:
10.1371/journal.pbio.3001279.g002
DOI:
10.1371/journal.pbio.3001279.g003
DOI:
10.1371/journal.pbio.3001279.g004
DOI:
10.1371/journal.pbio.3001279.g005
DOI:
10.1371/journal.pbio.3001279.g006
DOI:
10.1371/journal.pbio.3001279.g007
DOI:
10.1371/journal.pbio.3001279.g008
DOI:
10.1371/journal.pbio.3001279.s001
DOI:
10.1371/journal.pbio.3001279.s002
DOI:
10.1371/journal.pbio.3001279.s003
DOI:
10.1371/journal.pbio.3001279.s004
DOI:
10.1371/journal.pbio.3001279.s005
DOI:
10.1371/journal.pbio.3001279.s006
DOI:
10.1371/journal.pbio.3001279.s007
DOI:
10.1371/journal.pbio.3001279.s008
DOI:
10.1371/journal.pbio.3001279.s009
DOI:
10.1371/journal.pbio.3001279.s010
DOI:
10.1371/journal.pbio.3001279.s011
DOI:
10.1371/journal.pbio.3001279.s012
DOI:
10.1371/journal.pbio.3001279.s013
DOI:
10.1371/journal.pbio.3001279.s014
DOI:
10.1371/journal.pbio.3001279.s015
DOI:
10.1371/journal.pbio.3001279.s016
DOI:
10.1371/journal.pbio.3001279.s017
DOI:
10.1371/journal.pbio.3001279.s018
DOI:
10.1371/journal.pbio.3001279.s019
DOI:
10.1371/journal.pbio.3001279.s020
DOI:
10.1371/journal.pbio.3001279.s021
DOI:
10.1371/journal.pbio.3001279.s022
DOI:
10.1371/journal.pbio.3001279.r001
DOI:
10.1371/journal.pbio.3001279.r002
DOI:
10.1371/journal.pbio.3001279.r003
DOI:
10.1371/journal.pbio.3001279.r004
DOI:
10.1371/journal.pbio.3001279.r005
DOI:
10.1371/journal.pbio.3001279.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2126773-X
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