title: Exaggerated translation causes synaptic and behavioural aberrations associated with autism.
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.
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Santini
authors.forename: Thu N
authors.initials: TN
authors.lastname: Huynh
authors.forename: Andrew F
authors.initials: AF
authors.lastname: MacAskill
authors.forename: Adam G
authors.initials: AG
authors.lastname: Carter
authors.forename: Philippe
authors.initials: P
authors.lastname: Pierre
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
authors.forename: Hanoch
authors.initials: H
authors.lastname: Kaphzan
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D001522:Behavior, Animal / Q000187:drug effects; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006835:Hydrazones; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017072:Neostriatum / Q000378:metabolism; D009473:Neuronal Plasticity; D009574:Nitro Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D012315:RNA Caps / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000473:pathology*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C517852:4EGI-1 compound; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D006835:Hydrazones; D009574:Nitro Compounds; D012315:RNA Caps; D013844:Thiazoles