Autism-related deficits via dysregulated eIF4E-dependent translational control


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.


  1. 1

    Fombonne, E. Epidemiology of pervasive developmental disorders. Pediatr. Res. 65, 591–598 (2009)

    Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926–1945 (2004)

    CAS  Article  Google Scholar 

  4. 4

    Pause, A. et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature 371, 762–767 (1994)

    CAS  ADS  Article  Google Scholar 

  5. 5

    Koromilas, A. E., Lazaris-Karatzas, A. & Sonenberg, N. mRNAs containing extensive secondary structure in their 5′ non-coding region translate efficiently in cells overexpressing initiation factor eIF-4E. EMBO J. 11, 4153–4158 (1992)

    CAS  Article  Google Scholar 

  6. 6

    Banko, J. L. et al. The translation repressor 4E–BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. J. Neurosci. 25, 9581–9590 (2005)

    CAS  Article  Google Scholar 

  7. 7

    Zhou, J. & Parada, L. F. PTEN signaling in autism spectrum disorders. Curr. Opin. Neurobiol.. (2012)

  8. 8

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

    CAS  Article  Google Scholar 

  9. 9

    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)

    CAS  Article  Google Scholar 

  10. 10

    Jeste, S. S., Sahin, M., Bolton, P., Ploubidis, G. B. & Humphrey, A. Characterization of autism in young children with tuberous sclerosis complex. J. Child Neurol. 23, 520–525 (2008)

    Article  Google Scholar 

  11. 11

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

    CAS  ADS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

    Young, D. M., Schenk, A. K., Yang, S. B., Jan, Y. N. & Jan, L. Y. Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism. Proc. Natl Acad. Sci. USA 107, 11074–11079 (2010)

    CAS  ADS  Article  Google Scholar 

  14. 14

    Tsai, P. T. et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488, 647–651 (2012)

    CAS  ADS  Article  Google Scholar 

  15. 15

    O’Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012)

    ADS  Article  Google Scholar 

  16. 16

    Hoeffer, C. A. et al. Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav. 11, 332–341 (2012)

    CAS  Article  Google Scholar 

  17. 17

    Napoli, I. et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134, 1042–1054 (2008)

    CAS  Article  Google Scholar 

  18. 18

    Nowicki, S. T. et al. The Prader-Willi phenotype of fragile X syndrome. J. Dev. Behav. Pediatr. 28, 133–138 (2007)

    Article  Google Scholar 

  19. 19

    Rubenstein, J. L. & Merzenich, M. M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003)

    CAS  Article  Google Scholar 

  20. 20

    Uhlhaas, P. J. & Singer, W. Neuronal dynamics and neuropsychiatric disorders: toward a translational paradigm for dysfunctional large-scale networks. Neuron 75, 963–980 (2012)

    CAS  Article  Google Scholar 

  21. 21

    Cornew, L., Roberts, T. P., Blaskey, L. & Edgar, J. C. Resting-state oscillatory activity in autism spectrum disorders. J. Autism Dev. Disord. 42, 1884–1894 (2012)

    Article  Google Scholar 

  22. 22

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

    CAS  ADS  Article  Google Scholar 

  23. 23

    Luikart, B. W. et al. Pten knockdown in vivo increases excitatory drive onto dentate granule cells. J. Neurosci. 31, 4345–4354 (2011)

    CAS  Article  Google Scholar 

  24. 24

    Bateup, H. S., Takasaki, K. T., Saulnier, J. L., Denefrio, C. L. & Sabatini, B. L. Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J. Neurosci. 31, 8862–8869 (2011)

    CAS  Article  Google Scholar 

  25. 25

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

    ADS  Article  Google Scholar 

  26. 26

    Schmeisser, M. J. et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486, 256–260 (2012)

    CAS  ADS  Article  Google Scholar 

  27. 27

    Won, H. et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486, 261–265 (2012)

    CAS  ADS  Article  Google Scholar 

  28. 28

    Chao, H. T. et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010)

    CAS  ADS  Article  Google Scholar 

  29. 29

    Levinson, J. N. & El-Husseini, A. Building excitatory and inhibitory synapses: balancing neuroligin partnerships. Neuron 48, 171–174 (2005)

    CAS  Article  Google Scholar 

  30. 30

    Scattoni, M. L., Crawley, J. & Ricceri, L. Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders. Neurosci. Biobehav. Rev. 33, 508–515 (2009)

    Article  Google Scholar 

  31. 31

    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)

    CAS  Article  Google Scholar 

  32. 32

    Graff, J. R. et al. Therapeutic suppression of translation initiation factor eIF4E expression reduces tumor growth without toxicity. J. Clin. Invest. 117, 2638–2648 (2007)

    CAS  Article  Google Scholar 

  33. 33

    Glessner, J. T. et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569–573 (2009)

    CAS  ADS  Article  Google Scholar 

  34. 34

    Wang, K. et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459, 528–533 (2009)

    CAS  ADS  Article  Google Scholar 

  35. 35

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

    CAS  Article  Google Scholar 

  36. 36

    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)

    CAS  ADS  Article  Google Scholar 

  37. 37

    Chubykin, A. A. et al. Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron 54, 919–931 (2007)

    CAS  Article  Google Scholar 

  38. 38

    Dahlhaus, R. et al. Overexpression of the cell adhesion protein neuroligin-1 induces learning deficits and impairs synaptic plasticity by altering the ratio of excitation to inhibition in the hippocampus. Hippocampus 20, 305–322 (2010)

    CAS  Article  Google Scholar 

  39. 39

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

    CAS  Article  Google Scholar 

  40. 40

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

    CAS  Article  Google Scholar 

  41. 41

    Larsson, O. et al. Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc. Natl Acad. Sci. USA 109, 8977–8982 (2012)

    CAS  ADS  Article  Google Scholar 

  42. 42

    Levy, D. et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70, 886–897 (2011)

    CAS  Article  Google Scholar 

  43. 43

    Silverman, J. L., Yang, M., Lord, C. & Crawley, J. N. Behavioural phenotyping assays for mouse models of autism. Nature Rev. Neurosci. 11, 490–502 (2010)

    CAS  Article  Google Scholar 

  44. 44

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

    CAS  Article  Google Scholar 

  45. 45

    Bidinosti, M. et al. Postnatal deamidation of 4E–BP2 in brain enhances its association with raptor and alters kinetics of excitatory synaptic transmission. Mol. Cell 37, 797–808 (2010)

    CAS  Article  Google Scholar 

  46. 46

    Petroulakis, E. et al. p53-dependent translational control of senescence and transformation via 4E-BPs. Cancer Cell 16, 439–446 (2009)

    CAS  Article  Google Scholar 

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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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The authors declare no competing financial interests.

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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).

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