Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Exaggerated translation causes synaptic and behavioural aberrations associated with autism

Abstract

Autism spectrum disorders (ASDs) are an early onset, heterogeneous group of heritable neuropsychiatric disorders with symptoms that include deficits in social interaction skills, impaired communication abilities, and ritualistic-like repetitive behaviours1,2. One of the hypotheses for a common molecular mechanism underlying ASDs is altered translational control resulting in exaggerated protein synthesis3. Genetic variants in chromosome 4q, which contains the EIF4E locus, have been described in patients with autism4,5. Importantly, a rare single nucleotide polymorphism has been identified in autism that is associated with increased promoter activity in the EIF4E gene6. Here we show that genetically increasing the levels of eukaryotic translation initiation factor 4E (eIF4E) in mice7 results in exaggerated cap-dependent translation and aberrant behaviours reminiscent of autism, including repetitive and perseverative behaviours and social interaction deficits. Moreover, these autistic-like behaviours are accompanied by synaptic pathophysiology in the medial prefrontal cortex, striatum and hippocampus. The autistic-like behaviours displayed by the eIF4E-transgenic mice are corrected by intracerebroventricular infusions of the cap-dependent translation inhibitor 4EGI-1. Our findings demonstrate a causal relationship between exaggerated cap-dependent translation, synaptic dysfunction and aberrant behaviours associated with autism.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: eIF4E-transgenic mice exhibit increased eIF4E/eIF4G interactions and exaggerated cap-dependent translation.
Figure 2: eIF4E-transgenic mice exhibit ASD-like behaviours.
Figure 3: eIF4E-transgenic mice exhibit alterations in synaptic function, dendritic spine density and synaptic plasticity.
Figure 4: The cap-dependent translation inhibitor 4EGI-1 reverses ASD-like behaviours shown by eIF4E-transgenic mice.

Similar content being viewed by others

References

  1. Levitt, P. & Campbell, D. B. The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders. J. Clin. Invest. 119, 747–754 (2009)

    Article  CAS  Google Scholar 

  2. Rapin, I. & Tuchman, R. F. Autism: definition, neurobiology, screening, diagnosis. Pediatr. Clin. North Am. 55, 1129–1146 (2008)

    Article  Google Scholar 

  3. Kelleher, R. J. & Bear, M. F. The autistic neuron: troubled translation? Cell 135, 401–406 (2008)

    Article  CAS  Google Scholar 

  4. The Autism Genome Project Consortium. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genet. 39, 319–328 (2007)

  5. Yonan, A. L. et al. A genomewide screen of 345 families for autism-susceptibility loci. Am. J. Hum. Genet. 73, 886–897 (2003)

    Article  CAS  Google Scholar 

  6. Neves-Pereira, M. et al. Deregulation of EIF4E: a novel mechanism for autism. J. Med. Genet. 46, 759–765 (2009)

    Article  CAS  Google Scholar 

  7. Ruggero, D. et al. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nature Med. 10, 484–486 (2004)

    Article  CAS  Google Scholar 

  8. Moerke, N. J. et al. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 128, 257–267 (2007)

    Article  CAS  Google Scholar 

  9. Gingras, A. C. et al. Hierarchical phosphorylation of the translation inhibitor 4E–BP1. Genes Dev. 15, 2852–2864 (2001)

    Article  CAS  Google Scholar 

  10. Schmidt, E. K., Clavarino, G., Ceppi, M. & Pierre, P. SUnSET, a nonradioactive method to monitor protein synthesis. Nature Methods 6, 275–277 (2009)

    Article  CAS  Google Scholar 

  11. Hoeffer, C. A. et al. Inhibition of the interactions between eukaryotic initiation factors 4E and 4G impairs long-term associative memory consolidation but not reconsolidation. Proc. Natl Acad. Sci. USA 108, 3383–3388 (2011)

    Article  ADS  CAS  Google Scholar 

  12. Thomas, A. et al. Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology (Berl.) 204, 361–373 (2009)

    Article  CAS  Google Scholar 

  13. Peça, J. et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011)

    Article  ADS  Google Scholar 

  14. Hoeffer, C. A. et al. Removal of FKBP12 enhances mTOR-Raptor interactions, LTP, memory, and perseverative/repetitive behavior. Neuron 60, 832–845 (2008)

    Article  CAS  Google Scholar 

  15. Ehninger, D. et al. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nature Med. 14, 843–848 (2008)

    Article  CAS  Google Scholar 

  16. Moy, S. S. et al. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav. 3, 287–302 (2004)

    Article  CAS  Google Scholar 

  17. Zhou, J. et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J. Neurosci. 29, 1773–1783 (2009)

    Article  CAS  Google Scholar 

  18. Kwon, C.-H. et al. Pten regulates neuronal arborization and social interaction in mice. Neuron 50, 377–388 (2006)

    Article  CAS  Google Scholar 

  19. Fineberg, N. A. et al. Probing compulsive and impulsive behaviors, from animal models to endophenotypes: a narrative review. Neuropsychopharmacology 35, 591–604 (2010)

    Article  Google Scholar 

  20. Yizhar, O. et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011)

    Article  ADS  CAS  Google Scholar 

  21. Qiu, A., Adler, M., Crocetti, D., Miller, M. I. & Mostofsky, S. H. Basal ganglia shapes predict social, communication, and motor dysfunctions in boys with autism spectrum disorder. J. Am. Acad. Child Adolesc. Psychiatry 49, 539–551 (2010)

    PubMed  Google Scholar 

  22. Tabuchi, K. et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71–76 (2007)

    Article  ADS  CAS  Google Scholar 

  23. Calabresi, P., Maj, R., Pisani, A., Mercuri, N. B. & Bernardi, G. Long-term synaptic depression in the striatum: physiological and pharmacological characterization. J. Neurosci. 12, 4224–4233 (1992)

    Article  CAS  Google Scholar 

  24. Hou, L. et al. Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression. Neuron 51, 441–454 (2006)

    Article  CAS  Google Scholar 

  25. Huber, K. M., Kayser, M. S. & Bear, M. F. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288, 1254–1256 (2000)

    Article  ADS  CAS  Google Scholar 

  26. Auerbach, B. D., Osterweil, E. K. & Bear, M. F. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63–68 (2011)

    Article  ADS  CAS  Google Scholar 

  27. Ronesi, J. A. et al. Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nature Neurosci. 15, 431–440 (2012)

    Article  CAS  Google Scholar 

  28. Sharma, A. et al. Dysregulation of mTOR signaling in fragile X syndrome. J. Neurosci. 30, 694–702 (2010)

    Article  CAS  Google Scholar 

  29. Dölen, G. et al. Correction of fragile X syndrome in mice. Neuron 56, 955–962 (2007)

    Article  Google Scholar 

  30. Qin, M., Kang, J., Burlin, T. V., Jiang, C. & Smith, C. B. Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the Fmr1 null mouse. 25, 5087–5095 (2005)

  31. Franklin, K. B. J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates 3rd edn (Academic, 2007)

    Google Scholar 

  32. Errico, F. et al. The GTP-binding protein Rhes modulates dopamine signalling in striatal medium spiny neurons. Mol. Cell. Neurosci. 37, 335–345 (2008)

    Article  CAS  Google Scholar 

  33. Banko, J. L. et al. Behavioral alterations in mice lacking the translation repressor 4E-BP2. Neurobiol. Learn. Mem. 87, 248–256 (2007)

    Article  CAS  Google Scholar 

  34. Borgkvist, A. et al. Altered dopaminergic innervation and amphetamine response in adult Otx2 conditional mutant mice. Mol. Cell. Neurosci. 31, 293–302 (2006)

    Article  CAS  Google Scholar 

  35. Chévere-Torres, I., Maki, J. M., Santini, E. & Klann, E. Impaired social interactions and motor learning skills in tuberous sclerosis complex model mice expressing a dominant/negative form of tuberin. Neurobiol. Dis. 45, 156–164 (2012)

    Article  Google Scholar 

  36. Blundell, J. et al. Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J. Neurosci. 30, 2115–2129 (2010)

    Article  CAS  Google Scholar 

  37. Dumitriu, D., Rodriguez, A. & Morrison, J. H. High-throughput, detailed, cell-specific neuroanatomy of dendritic spines using microinjection and confocal microscopy. Nature Protocols 6, 1391–1411 (2011)

    Article  CAS  Google Scholar 

  38. Chalifoux, J. R. & Carter, A. G. GABAB receptors modulate NMDA receptor calcium signals in dendritic spines. Neuron 66, 101–113 (2010)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank J. LeDoux and members of his laboratory for their technical support and suggestions. We would also like to thank D. St Clair and Z. Miedzybrodzka for their comments on the manuscript. This research was supported by National Institutes of Health (NIH) grants NS034007, NS047384 and NS078718, and Department of Defense CDMRP award W81XWH-11-1-0389 (E.K.), NIH grant CA154916 (D.R.) and the Wellcome Trust (A.F.M.).

Author information

Authors and Affiliations

Authors

Contributions

The study was directed by E.K. and conceived and designed by E.S. and E.K. E.S. performed the molecular, behavioural and electrophysiological experiments. T.N.H. performed behavioural experiments. A.F.M. and A.G.C. performed the dendritic spine-density experiments. P.P. contributed the anti-puromycin (12D10) antibody. D.R. contributed with reagents and expertise concerning translation control by eIF4E. H.K. performed the cortical whole-cell electrophysiological experiments. The manuscript was written by E.S. and E.K. and edited by all of the authors.

Corresponding author

Correspondence to Eric Klann.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-4. (PDF 2067 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Santini, E., Huynh, T., MacAskill, A. et al. Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 493, 411–415 (2013). https://doi.org/10.1038/nature11782

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11782

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing