Autism-related deficits via dysregulated eIF4E-dependent translational control
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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. 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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MIA alters key components of the TSC/mTOR signaling pathway with ultimate activation of the translation initiation factor EIF4E, which is predicted to alter regulation of neural progenitor cell divisions during midgestation.
“Consistently, we found that MIA alters key components of the TSC/mTOR signaling pathway with ultimate activation of the translation initiation factor EIF4E which is predicted to alter the regulation of neural progenitor cell divisions during midgestation [127, 156–158].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [158]
This hypothesis has been further elaborated by Santini and Klann and others, with new evidence supporting the crucial role of cap-dependent translation protein EIF4E in ASD pathophysiology.
“This hypothesis has been further elaborated by Santini and Klann and others, with new evidence supporting the crucial role of cap-dependent translation protein EIF4E79, 88, 100, 101 in ASD pathophysiology.77”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [100]
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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
- Venue
- Nature
- Published
- 2012-11-21
- Volume
- 493
- Issue
- 7432
- Pages
- 371-377
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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