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Autism-related deficits via dysregulated eIF4E-dependent translational control.

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.

Pubmed ID: 23172145

Authors

  • Gkogkas CG
  • Khoutorsky A
  • Ran I
  • Rampakakis E
  • Nevarko T
  • Weatherill DB
  • Vasuta C
  • Yee S
  • Truitt M
  • Dallaire P
  • Major F
  • Lasko P
  • Ruggero D
  • Nader K
  • Lacaille JC
  • Sonenberg N

Journal

Nature

Publication Data

January 17, 2013

Associated Grants

  • Agency: Canadian Institutes of Health Research, Id: MOP-10848
  • Agency: Canadian Institutes of Health Research, Id: MOP-114994
  • Agency: Canadian Institutes of Health Research, Id: MOP-44050
  • Agency: Canadian Institutes of Health Research, Id: MOP-93679
  • Agency: NCI NIH HHS, Id: R01 CA140456
  • Agency: NCI NIH HHS, Id: R01 CA140456
  • Agency: NCI NIH HHS, Id: R01 CA154916
  • Agency: NCI NIH HHS, Id: R01 CA154916
  • Agency: NIGMS NIH HHS, Id: R01 GM088813

Mesh Terms

  • Animals
  • Autistic Disorder
  • Cell Adhesion Molecules, Neuronal
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Male
  • Mice
  • Mice, Knockout
  • Phenotype
  • Protein Biosynthesis
  • Synapses