Exaggerated translation causes synaptic and behavioural aberrations associated with autism

Emanuela Santini, Thu N. Huynh, Andrew F. MacAskill, Adam Carter, Philippe Pierre, Davide Ruggero, Hanoch Kaphzan, Eric Klann

Research output: Contribution to journalArticle

Abstract

Autism spectrum disorders (ASDs) are an early onset, heterogeneous group of heritable neuropsychiatric disorders with symptoms that include deficits in social interaction skills, impaired communication abilities, and ritualistic-like repetitive behaviours. One of the hypotheses for a common molecular mechanism underlying ASDs is altered translational control resulting in exaggerated protein synthesis. Genetic variants in chromosome 4q, which contains the EIF4E locus, have been described in patients with autism. Importantly, a rare single nucleotide polymorphism has been identified in autism that is associated with increased promoter activity in the EIF4E gene. Here we show that genetically increasing the levels of eukaryotic translation initiation factor 4E (eIF4E) in mice results in exaggerated cap-dependent translation and aberrant behaviours reminiscent of autism, including repetitive and perseverative behaviours and social interaction deficits. Moreover, these autistic-like behaviours are accompanied by synaptic pathophysiology in the medial prefrontal cortex, striatum and hippocampus. The autistic-like behaviours displayed by the eIF4E-transgenic mice are corrected by intracerebroventricular infusions of the cap-dependent translation inhibitor 4EGI-1. Our findings demonstrate a causal relationship between exaggerated cap-dependent translation, synaptic dysfunction and aberrant behaviours associated with autism.

Original languageEnglish (US)
Pages (from-to)411-415
Number of pages5
JournalNature
Volume493
Issue number7432
DOIs
StatePublished - Jan 17 2013

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Autistic Disorder
Eukaryotic Initiation Factor-4E
Interpersonal Relations
Intraventricular Infusions
Eukaryotic Initiation Factors
Aptitude
Prefrontal Cortex
Transgenic Mice
Single Nucleotide Polymorphism
Hippocampus
Chromosomes
Communication
Genes
Proteins

ASJC Scopus subject areas

  • General

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Exaggerated translation causes synaptic and behavioural aberrations associated with autism. / Santini, Emanuela; Huynh, Thu N.; MacAskill, Andrew F.; Carter, Adam; Pierre, Philippe; Ruggero, Davide; Kaphzan, Hanoch; Klann, Eric.

In: Nature, Vol. 493, No. 7432, 17.01.2013, p. 411-415.

Research output: Contribution to journalArticle

Santini, E, Huynh, TN, MacAskill, AF, Carter, A, Pierre, P, Ruggero, D, Kaphzan, H & Klann, E 2013, 'Exaggerated translation causes synaptic and behavioural aberrations associated with autism', Nature, vol. 493, no. 7432, pp. 411-415. https://doi.org/10.1038/nature11782
Santini E, Huynh TN, MacAskill AF, Carter A, Pierre P, Ruggero D et al. Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature. 2013 Jan 17;493(7432):411-415. https://doi.org/10.1038/nature11782
Santini, Emanuela ; Huynh, Thu N. ; MacAskill, Andrew F. ; Carter, Adam ; Pierre, Philippe ; Ruggero, Davide ; Kaphzan, Hanoch ; Klann, Eric. / Exaggerated translation causes synaptic and behavioural aberrations associated with autism. In: Nature. 2013 ; Vol. 493, No. 7432. pp. 411-415.
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