Autism-related deficits via dysregulated eIF4E-dependent translational control

Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T, Weatherill DB, Vasuta C, Yee S, Truitt M, Dallaire P, Major F, …, Sonenberg N · 2013 · Nature · Atlas ID GKO2013

What this study shows

Mice lacking 4E-BP2, the main brain brake on eIF4E downstream of mTORC1, showed autism-like behaviours: reduced social approach in the three-chamber test, more self-grooming and marble burying, and more ultrasonic calls as pups. Polysome profiling of hippocampus showed that, of 24 autism-linked mRNAs tested, only the neuroligin 1-4 mRNAs shifted to heavier polysomes in the knockout, with no change in their mRNA levels or in global protein synthesis; eIF4E-overexpressing mice showed the same neuroligin shift. Knockout neurons had larger excitatory than inhibitory synaptic charge transfer, raising the excitation/inhibition ratio. Five days of brain infusion of 4EGI-1, which blocks eIF4E binding to eIF4G, brought cap-bound eIF4E/eIF4G and neuroligin levels back to normal and reversed the social deficit, and knocking down neuroligin 1 (but not neuroligin 2) partly restored social behaviour. Boundary: mouse genetic models (male mice for behaviour); mTOR itself was not manipulated; the link to human autism is by analogy.

Abstract

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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.

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At a glance

Evidence type	A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Eif4ebp2 knockout mice and betaT-Eif4e (eIF4E-overexpressing) mice; hippocampal slices and slice cultures; MEF reporter assays; icv 4EGI-1 and lentiviral shRNA); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type	4 - Animal Study
Model system	Eif4ebp2 knockout mice and betaT-Eif4e (eIF4E-overexpressing) mice; hippocampal slices and slice cultures; MEF reporter assays; icv 4EGI-1 and lentiviral shRNA
Journal	Nature
Year	2013
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1038/nature11628 · PMID 23172145 · Free full text (PMC4133997)

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	Eif4ebp2 knockout; eIF4E overexpression; 4EGI-1 (icv); Nlgn1/Nlgn2 knockdown
Target	4E-BP2 / eIF4E (eIF4F complex)
Model	Mouse
Effect	Loss of 4E-BP2 increased neuroligin translation and E/I ratio and caused autism-like behaviour; eIF4F inhibition reversed it

In the Atlas

Cite this paper

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Gkogkas, C. G., Khoutorsky, A., Ran, I., Rampakakis, E., Nevarko, T., Weatherill, D. B., Vasuta, C., Yee, S., Truitt, M., Dallaire, P., Major, F., Lasko, P., Ruggero, D., Nader, K., Lacaille, J. C., & Sonenberg, N. (2013). Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature. https://doi.org/10.1038/nature11628

@article{GKO2013,
  author       = {Gkogkas, C. G. and Khoutorsky, A. and Ran, I. and Rampakakis, E. and Nevarko, T. and Weatherill, D. B. and Vasuta, C. and Yee, S. and Truitt, M. and Dallaire, P. and Major, F. and Lasko, P. and Ruggero, D. and Nader, K. and Lacaille, J. C. and Sonenberg, N.},
  title        = {{Autism-related deficits via dysregulated eIF4E-dependent translational control}},
  journal      = {Nature},
  year         = {2013},
  doi          = {10.1038/nature11628},
  note         = {PMID: 23172145},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record GKO2013) [Data set]. https://mtor-atlas.org/study/GKO2013/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_GKO2013,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record GKO2013},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/GKO2013/},
  doi          = {10.5281/zenodo.22059963}
}

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