PMID- 23172145
OWN - NLM
STAT- MEDLINE
DCOM- 20130304
LR  - 20220309
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 493
IP  - 7432
DP  - 2013 Jan 17
TI  - Autism-related deficits via dysregulated eIF4E-dependent translational control.
PG  - 371-7
LID - 10.1038/nature11628 [doi]
AB  - Hyperconnectivity of neuronal circuits due to increased synaptic protein 
      synthesis is thought to cause autism spectrum disorders (ASDs). The mammalian 
      target of rapamycin (mTOR) is strongly implicated in ASDs by means of upstream 
      signalling; however, downstream regulatory mechanisms are ill-defined. Here we 
      show that knockout of the eukaryotic translation initiation factor 4E-binding 
      protein 2 (4E-BP2)-an eIF4E repressor downstream of mTOR-or eIF4E overexpression 
      leads to increased translation of neuroligins, which are postsynaptic proteins 
      that are causally linked to ASDs. Mice that have the gene encoding 4E-BP2 
      (Eif4ebp2) knocked out exhibit an increased ratio of excitatory to inhibitory 
      synaptic inputs and autistic-like behaviours (that is, social interaction 
      deficits, altered communication and repetitive/stereotyped behaviours). 
      Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, 
      but not neuroligin 2, protein levels restores the normal excitation/inhibition 
      ratio and rectifies the social behaviour deficits. Thus, translational control by 
      eIF4E regulates the synthesis of neuroligins, maintaining the 
      excitation-to-inhibition balance, and its dysregulation engenders ASD-like 
      phenotypes.
FAU - Gkogkas, Christos G
AU  - Gkogkas CG
AD  - Department of Biochemistry & Goodman Cancer Research Centre, McGill University, 
      Montreal, Quebec H3A 1A3, Canada.
FAU - Khoutorsky, Arkady
AU  - Khoutorsky A
FAU - Ran, Israeli
AU  - Ran I
FAU - Rampakakis, Emmanouil
AU  - Rampakakis E
FAU - Nevarko, Tatiana
AU  - Nevarko T
FAU - Weatherill, Daniel B
AU  - Weatherill DB
FAU - Vasuta, Cristina
AU  - Vasuta C
FAU - Yee, Stephanie
AU  - Yee S
FAU - Truitt, Morgan
AU  - Truitt M
FAU - Dallaire, Paul
AU  - Dallaire P
FAU - Major, Francois
AU  - Major F
FAU - Lasko, Paul
AU  - Lasko P
FAU - Ruggero, Davide
AU  - Ruggero D
FAU - Nader, Karim
AU  - Nader K
FAU - Lacaille, Jean-Claude
AU  - Lacaille JC
FAU - Sonenberg, Nahum
AU  - Sonenberg N
LA  - eng
GR  - R01 GM088813/GM/NIGMS NIH HHS/United States
GR  - MOP-10848/CAPMC/CIHR/Canada
GR  - MOP-44050/CAPMC/CIHR/Canada
GR  - MOP-93679/CAPMC/CIHR/Canada
GR  - R01 CA140456/CA/NCI NIH HHS/United States
GR  - MOP-114994/CAPMC/CIHR/Canada
GR  - R01 CA154916/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20121121
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Cell Adhesion Molecules, Neuronal)
RN  - 0 (Eif4ebp2 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (neuroligin 1)
SB  - IM
CIN - Nat Rev Drug Discov. 2013 Jan;12(1):21. PMID: 23237920
CIN - Nat Rev Neurosci. 2013 Feb;14(2):79. PMID: 23324663
MH  - Animals
MH  - Autistic Disorder/*genetics/*physiopathology
MH  - Cell Adhesion Molecules, Neuronal/genetics/metabolism
MH  - Eukaryotic Initiation Factor-4E/antagonists & inhibitors/*metabolism
MH  - Eukaryotic Initiation Factors/deficiency/genetics/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Phenotype
MH  - *Protein Biosynthesis
MH  - Synapses/metabolism
PMC - PMC4133997
MID - NIHMS504392
EDAT- 2012/11/23 06:00
MHDA- 2013/03/05 06:00
PMCR- 2014/08/15
CRDT- 2012/11/23 06:00
PHST- 2012/01/10 00:00 [received]
PHST- 2012/09/28 00:00 [accepted]
PHST- 2012/11/23 06:00 [entrez]
PHST- 2012/11/23 06:00 [pubmed]
PHST- 2013/03/05 06:00 [medline]
PHST- 2014/08/15 00:00 [pmc-release]
AID - nature11628 [pii]
AID - 10.1038/nature11628 [doi]
PST - ppublish
SO  - Nature. 2013 Jan 17;493(7432):371-7. doi: 10.1038/nature11628. Epub 2012 Nov 21.