Autism-related deficits via dysregulated eIF4E-dependent translational control

Abstract

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.

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Figure 1: Social interaction deficits, repetitive behaviour and elevated USVs in Eif4ebp2 knockout mice.
Figure 2: Enhanced eIF4E-dependent translation of neuroligin mRNAs.
Figure 3: Excitation is increased to a larger extent than inhibition in Eif4ebp2 knockout mice.
Figure 4: Rescue of excitatory/inhibitory synaptic activity imbalance and social deficits in Eif4ebp2 knockout mice by inhibiting the eIF4E–eIF4G interaction.
Figure 5: Knockdown of neuroligin 1 rescues the excitatory/inhibitory synaptic activity imbalance and social deficits in Eif4ebp2 knockout mice.

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Acknowledgements

This work was supported by the Canadian Institutes of Health Research (N.S., MOP-114994; J.-C.L., MOP-10848; P.D. and F.M., MOP-93679; and P.L. and N.S., MOP-44050), Autism Speaks (Grant 7109 to N.S.), and the Fonds de la Recherche en Santé du Québec (J.-C.L. FRSQ; Groupe de Recherche sur le Système Nerveux Central), and the National Institutes of Health (D.R.; NIH RO1 CA154916 and NIH RO1 CA140456). D.R. is a Leukemia & Lymphoma Society Scholar. J.-C.L. is the recipient of the Canada Research Chair in Cellular and Molecular Neurophysiology. I.R. was supported by a Fellowship of the Savoy Foundation. We thank Y. Svitkin, A. Parsyan, E. Petroulakis, R. Karni and V. Polunovski for advice; K. Gamache, A. Sylvestre, S. Perreault, C. Lister and I. Harvey for technical assistance; T. Alain for assistance with lentiviral titration; S. Hamdani for assistance with USVs; and W. Sossin and P. Skehel for critical reading of the manuscript.

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C.G.G. and N.S. conceived and designed this study, wrote the manuscript, supervised and coordinated the project. C.G.G. carried out behavioural, biochemical and imaging experiments, data and statistical analysis; C.G.G., A.K., I.R., D.B.W. and C.V. carried out electrophysiology experiments and data analysis; T.N. and S.Y. conducted biochemical experiments and data analysis; E.R. and I.R. carried out statistical analysis; P.D. and F.M. carried out bioinformatics analysis; M.T. and D.R. provided critical insight and reagents, and edited the manuscript; P.L. supervised the project and edited the manuscript; and K.N. contributed to the design of behavioural experiments, edited the manuscript and supervised the project; J-C.L. supervised, conceived and designed the electrophysiological experiments, edited the manuscript and supervised the project.

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Correspondence to Jean-Claude Lacaille or Nahum Sonenberg.

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Gkogkas, C., Khoutorsky, A., Ran, I. et al. Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493, 371–377 (2013). https://doi.org/10.1038/nature11628

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