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. Mice lacking 4E-BP2, an eIF4E repressor, display increased translation of neuroligins; the mice also show autism-related behaviours and alterations in hippocampal synaptic activity, and these are reversed by normalization of eIF4E activity or neuroligin 1 levels. Aberrant protein synthesis has been hypothesized as one causal mechanism of autism spectrum disorders (ASDs), but the details of which pathways are disrupted remain unknown. Disruption of eIF4E, a key factor for translation initiation, has been associated with human autism, and now two independent papers implicate excessive cap-dependent translation in synaptic and ASD-related behavioural deficits in mice. Nahum Sonenberg and colleagues show that mice lacking 4E-BP2, an eIF4E repressor, display increased translation of neuroligins, synaptic proteins strongly implicated in autism. The mice also display ASD-related behaviors and alterations in hippocampal synaptic activity, which are reversed by normalization of eIF4E activity or neuroligin 1 levels. Eric Klann and colleagues show that mice overexpressing eIF4E also display ASD-related behaviours and altered synaptic activity in the hippocampus, prefrontal cortex and striatum, and that some phenotypes can be rescued with the cap-dependent translation inhibitor 4EGI-1. The converging results from these two studies implicate cap-dependent translation as a potential therapeutic target for treatment of ASD-related symptoms.

Autism-related deficits via dysregulated eIF4E-dependent translational control