Autism-related deficits via dysregulated eIF4E-dependent translational control

Abstract

Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is postulated to cause Autism Spectrum Disorders (ASD). The mammalian target of rapamycin (mTOR) is strongly implicated in ASD via upstream signaling. However, downstream regulatory mechanisms are ill-defined. We show that knockout (KO) of the eukaryotic translation Initiation Factor 4E-Binding Protein 2 (4E-BP2), an eIF4E-repressor downstream of mTOR, or eIF4E overexpression lead to increased translation of neuroligins, which are post-synaptic proteins that are causally linked to ASD. 4E-BP2-KO mice exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviors: social interaction deficits, altered communication and repetitive/stereotyped behaviors. Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2 protein amounts, restore the normal excitation/inhibition ratio and rectify the social behavior deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation to inhibition balance, and its dysregulation engenders ASD-like phenotypes.

Shank mutant mice as an animal model of autism

“…By contrast, NLGN2 tends to locate preferentially to inhibitory synapses via an interaction with gephyrin [46]. A recent paper by Gkogkas et al [47] provides a promising link between NLGN and the mGluR theory. The authors investigated a model of excessive protein synthesis by eukaryotic translation initiation factor 4E (eIF4E) overexpression or depression (knockout of eIF4E-binding protein 2) and found that it resulted in over-translation of NLGN, increased excitatory-to-inhibitory transmission ratio and autism-like behavioural symptoms.…”

“…B 369: 20130143 is enhanced, the excitatory/inhibitory (E/I) ratio is increased. Reduction of NLGN1 levels using siRNA restored E/I balance and reversed deficits in social interaction behaviour [47]. Another example is the case of the Shank2 KO; it was shown that acute administration of either the NMDAR partial agonist D-cycloserine or an mGluR5-positive allosteric modulator (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide) could rescue the electrophysiological and social impairments in the KO mice [67].…”

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

“…Answering these questions is difficult because the disorder is multifactorial in nature with multiple genetic variants and environmental factors contributing to the core symptoms (10)(11)(12)(13). To face this challenge, extensive efforts have been made to identify the targeting and functional convergence of the autism-risk genes, such as those involved in translation regulation (14)(15)(16) and long-range connectivity among different brain regions (17)(18)(19). These targets and functions provide a better biological basis for elucidating the causal paths between risk genes and the disorders of autism.…”

Molecular mechanism of the dual activity of 4EGI-1: Dissociating eIF4G from eIF4E but stabilizing the binding of unphosphorylated 4E-BP1

“…Altered regulation of translation initiation has been linked to prion formation (9) and to several human diseases, including autism (10) and cancer (11). eIF4E is overexpressed in a variety of tumor cells (12,13).…”