Cited by 528Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchRNA and protein synthesis mechanisms

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Autism-related deficits via dysregulated eIF4E-dependent translational control

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Gkogkas, Christos G., Khoutorsky, Arkady, Ran, Israeli, Rampakakis, Emmanouil, Nevarko, Tatiana, Weatherill, Daniel B., Vasuta, Cristina, Yee, Stephanie, Truitt, Morgan, Dallaire, Paul, Major, François, Lasko, Paul, Ruggero, Davide, Nader, Karim, Lacaille, Jean-Claude, Sonenberg, Nahum·2013·Nature

DOI 10.1038/nature11628PMC PMC4133997

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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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Authors: 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.
Affiliations: McGill University (CA)
Université de Montréal (CA)
University of California, San Francisco (US)
Institute for Research in Immunology and Cancer (CA)
Corresponding author: Lacaille, Jean-Claude
Sonenberg, Nahum
ORCID: Gkogkas, Christos G.
Khoutorsky, Arkady
Rampakakis, Emmanouil
Yee, Stephanie
Truitt, Morgan
Major, François
Lasko, Paul
Ruggero, Davide
Nader, Karim
Lacaille, Jean-Claude
Sonenberg, Nahum
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2012-11-21
Volume: 493
Issue: 7432
Pages: 371-377
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature11628
PMC: PMC4133997
OpenAlex: W2048862315
Cited by: 522
References: 46
Citations by year: 2026: 20 · 2025: 31 · 2024: 23 · 2023: 29 · 2022: 31 · 2021: 27 · 2020: 42 · 2019: 45 · 2018: 33 · 2017: 37 · 2016: 49 · 2015: 59 · 2014: 53 · 2013: 40 · 2012: 2
FWCI: 29.87
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
eScholarship@McGill (McGill) (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: Canadian Institutes of Health Research (MOP-114994), MOP93679, MOP-10848, MOP-44050)
National Cancer Institute (R01CA140456, R01CA154916)
National Institute of General Medical Sciences (R01GM088813)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords: autism spectrum disorder, eIF4E, 4E-BP2, translational regulation, mTOR signaling, neuroligin-1, neuroligin-2, synaptic protein synthesis, excitation-inhibition balance, social interaction deficits, cap-dependent translation, 4EGI-1
MeSH terms: Animals, Autistic Disorder, Male, Phenotype, Synapses, Protein Biosynthesis, Cell Adhesion Molecules, Neuronal, Mice, Knockout, Eukaryotic Initiation Factor-4E, Eukaryotic Initiation Factors, Mice

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Autism-related deficits via dysregulated eIF4E-dependent translational control

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