Exaggerated Translation Causes Synaptic and Behavioral Aberrations Associated with Autism

Department of Urology, School of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
Nature (Impact Factor: 41.46). 12/2012; 493(7432). DOI: 10.1038/nature11782
Source: PubMed


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.

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    • "In support of this is the widespread and extensive lengthening of 3' UTRs (untranslated regions) that are targeted by miRNAs in the mammalian brain [58] . Targeting the dysregulation of protein synthesis opens up a novel approach for the effective treatment of some neuropsychiatric disorders [55] [56] [57] [59] . "
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    • "Remarkably, suppression of neuroligin 1 partially reversed the behavioral phenotypes in these mice (Gkogkas et al., 2013). In a parallel study, overexpression of eIF4E similarly resulted in defective social behavior and hippocampal physiology (Santini et al., 2013). These studies have illuminated translational regulation pathways as crucial mediators of higher order cognitive function and suggest that manipulation of these pathways may be pharmacological targets for treating autism. "
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    • "An important regulatory action was recently described in the other component of this pathway, the downstream effectors of mTOR. Signaling molecules in the downstream of the mTOR pathway have been demonstrated to play crucial roles in ASD pathogenesis, further highlighting its role (37, 38). Furthermore, 4E-BP2 inhibits protein translation by competing with eIF4G for eIF4E binding. "
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