title: Autism-related deficits via dysregulated eIF4E-dependent translational control.
abstract: 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.
authors.affiliation: Department of Biochemistry & Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Christos G
authors.initials: CG
authors.lastname: Gkogkas
authors.forename: Arkady
authors.initials: A
authors.lastname: Khoutorsky
authors.forename: Israeli
authors.initials: I
authors.lastname: Ran
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Rampakakis
authors.forename: Tatiana
authors.initials: T
authors.lastname: Nevarko
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Weatherill
authors.forename: Cristina
authors.initials: C
authors.lastname: Vasuta
authors.forename: Stephanie
authors.initials: S
authors.lastname: Yee
authors.forename: Morgan
authors.initials: M
authors.lastname: Truitt
authors.forename: Paul
authors.initials: P
authors.lastname: Dallaire
authors.forename: François
authors.initials: F
authors.lastname: Major
authors.forename: Paul
authors.initials: P
authors.lastname: Lasko
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
authors.forename: Karim
authors.initials: K
authors.lastname: Nader
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lacaille
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D014176:Protein Biosynthesis; D013569:Synapses / Q000378:metabolism
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C491255:Eif4ebp2 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; C093438:neuroligin 1