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.

Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2

Nature volume 486, pages 256–260 (2012)Cite this article

Subjects

This article has been updated

Abstract

Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour1. Mutations in synaptic proteins such as neuroligins2,3, neurexins4, GKAPs/SAPAPs5 and ProSAPs/Shanks6,7,8,9,10 were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion11,12. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2−/− mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2−/− mutants with ProSAP2/Shank3αβ−/− mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Cyto-architechtural and molecular changes in ProSAP1/Shank2 −/− mouse brain.
Figure 2: Imbalanced hippocampal glutamatergic synaptic transmission in ProSAP1/Shank2 −/− mice.
Figure 3: Increased locomotor activity and stereotypical behaviours in ProSAP1/Shank2 −/− mice.
Figure 4: Abnormalities in social and vocal behaviour of ProSAP1/Shank2 −/− mice in the resident–intruder test and during the interaction of a male with an oestrus female.

Change history

  • 13 June 2011

    A present address was added to the affiliations.

References

  1. Abrahams, B. S. & Geschwind, D. H. Advances in autism genetics: on the threshold of a new neurobiology. Nature Rev. Genet. 9, 341–355 (2008)

    Article  CAS  Google Scholar 

  2. Jamain, S. et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genet. 34, 27–29 (2003)

    Article  CAS  Google Scholar 

  3. Etherton, M. R., Tabuchi, K., Sharma, M., Ko, J. & Südhof, T. C. An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus. EMBO J. 30, 2908–2919 (2011)

    Article  CAS  Google Scholar 

  4. Kim, H. G. et al. Disruption of neurexin 1 associated with autism spectrum disorder. Am. J. Hum. Genet. 82, 199–207 (2008)

    Article  CAS  Google Scholar 

  5. Pinto, D. et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368–372 (2010)

    Article  ADS  CAS  Google Scholar 

  6. Moessner, R. et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am. J. Hum. Genet. 81, 1289–1297 (2007)

    Article  CAS  Google Scholar 

  7. Gauthier, J. et al. Novel de novo SHANK3 mutation in autistic patients. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 150B, 421–424 (2009)

    Article  CAS  Google Scholar 

  8. Durand, C. M. et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genet. 39, 25–27 (2007)

    Article  CAS  Google Scholar 

  9. Berkel, S. et al. Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nature Genet. 42, 489–491 (2010)

    Article  MathSciNet  CAS  Google Scholar 

  10. Leblond, C. S. et al. Genetic and functional analyses of SHANK2 mutations provide evidence for a multiple hit model of autism spectrum disorders. PLoS Genet. 8, e1002521 (2012)

    Article  CAS  Google Scholar 

  11. Baron, M. K. et al. An architectural framework that may lie at the core of the postsynaptic density. Science 311, 531–535 (2006)

    Article  ADS  CAS  Google Scholar 

  12. Grabrucker, A. M. et al. Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation. EMBO J. 30, 569–581 (2011)

    Article  CAS  Google Scholar 

  13. Toro, R. et al. Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends Genet. 26, 363–372 (2010)

    Article  CAS  Google Scholar 

  14. Grabrucker, A. M., Schmeisser, M. J., Schoen, M. & Boeckers, T. M. Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies. Trends Cell Biol. 21, 594–603 (2011)

    Article  CAS  Google Scholar 

  15. Hamdan, F. F. et al. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am. J. Hum. Genet. 88, 306–316 (2011)

    Article  CAS  Google Scholar 

  16. Bozdagi, O. et al. Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol. Autism 1, 15 (2010)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  18. Wang, X. et al. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum. Mol. Genet. 20, 3093–3108 (2011)

    Article  CAS  Google Scholar 

  19. Bangash, M. A. et al. Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism. Cell 145, 758–772 (2011)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  21. Gemelli, T. et al. Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol. Psychiatry 59, 468–476 (2006)

    Article  CAS  Google Scholar 

  22. Boeckers, T. M. et al. Proline-rich synapse-associated protein-1/cortactin binding protein 1 (ProSAP1/CortBP1) is a PDZ-domain protein highly enriched in the postsynaptic density. J. Neurosci. 19, 6506–6518 (1999)

    Article  CAS  Google Scholar 

  23. Berkel, S. et al. Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology. Hum. Mol. Genet. 21, 344–357 (2012)

    Article  CAS  Google Scholar 

  24. 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 

  25. Pearson, B. L. et al. Motor and cognitive stereotypies in the BTBR T+tf/J mouse model of autism. Genes Brain Behav. 10, 228–235 (2011)

    Article  CAS  Google Scholar 

  26. Hung, A. Y. et al. Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J. Neurosci. 28, 1697–1708 (2008)

    Article  CAS  Google Scholar 

  27. Wohr, M., Roullet, F. I., Hung, A. Y., Sheng, M. & Crawley, J. N. Communication impairments in mice lacking Shank1: reduced levels of ultrasonic vocalizations and scent marking behavior. PLoS ONE 6, e20631 (2011)

    Article  ADS  CAS  Google Scholar 

  28. Silverman, J. L. et al. Sociability and motor functions in Shank1 mutant mice. Brain Res. 1380, 120–137 (2011)

    Article  CAS  Google Scholar 

  29. Ey, E., Leblond, C. S. & Bourgeron, T. Behavioral profiles of mouse models for autism spectrum disorders. Autism Res. 4, 5–16 (2011)

    Article  Google Scholar 

  30. Schmeisser, M. J., Grabrucker, A. M., Bockmann, J. & Boeckers, T. M. Synaptic cross-talk between N-methyl-D-aspartate receptors and LAPSER1-beta-catenin at excitatory synapses. J. Biol. Chem. 284, 29146–29157 (2009)

    Article  CAS  Google Scholar 

  31. Boeckers, T. M. et al. Proline-rich synapse-associated protein-1/cortactin binding protein 1 (ProSAP1/CortBP1) is a PDZ-domain protein highly enriched in the postsynaptic density. J. Neurosci. 19, 6506–6518 (1999)

    Article  CAS  Google Scholar 

  32. Grabrucker, A. M. et al. Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation. EMBO J. 30, 569–581 (2011)

    Article  CAS  Google Scholar 

  33. Zitzer, H., Hoenck, H. H., Baechner, D., Richter, D. & Kreienkamp, H. J. Somatostatin receptor interacting protein defines a novel family of multidomain proteins present in human and rodent brain. J. Biol. Chem. 274, 32997–33001 (1999)

    Article  CAS  Google Scholar 

  34. Schmitz, D., Mellor, J., Breustedt, J. & Nicoll, R. A. Presynaptic kainate receptors impart an associative property to hippocampal mossy fiber long-term potentiation. Nature Neurosci. 6, 1058–1063 (2003)

    Article  CAS  Google Scholar 

  35. Wishaw, I. Q., Haun, F. & Kolb, B. in Modern Techniques in Neuroscience (eds Windhorst, U. & Johansson, H. ) 1243–1275 (Springer, 1999)

    Book  Google Scholar 

  36. Rogers, D. C. et al. Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm. Genome 8, 711–713 (1997)

    Article  CAS  Google Scholar 

  37. Nadler, J. J. et al. Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav. 3, 303–314 (2004)

    Article  CAS  Google Scholar 

  38. Bourgeron, T., Jamain, S. & Granon, S. in Contemporary Clinical Neuroscience: Transgenic and Knockout Models of Neuropsychiatric Disorders (eds Fisch, G.S. & Flint, J. ) 151–174 (Humana Press, 2006)

    Book  Google Scholar 

  39. Montag-Sallaz, M., Schachner, M. & Montag, D. Misguided axonal projections, NCAM180 mRNA upregulation, and altered behavior in mice deficient for the close homolog of L1 (CHL1). Mol. Cell. Biol. 22, 7967–7981 (2002)

    Article  CAS  Google Scholar 

  40. Scattoni, M. L. Unusual repertoire of vocalizations in adult BTBR T+tf/J mice during three types of social encounters. Genes Brain Behav. 10, 44–56 (2011)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Manz, R. Zienecker, S. Gerlach-Arbeiter, N. Damm, H. Riederer, C. Jean, S. Rieckmann, S. Hochmuth and K. Sowa for technical assistance. M.J.S., A.-L.J. and P.T.U. are members of the International Graduate School in Molecular Medicine at Ulm University. M.J.S. is further supported by Baustein 3.2 (L.SBN.0081), E.E. by the Fondation de France and the Agence Nationale de la Recherche (ANR) FLEXNEURIM (ANR09BLAN034003), S.W. and A.V.S. by the Deutsche Forschungsgemeinschaft (DFG) (GRK 1123), A.M.G. by Baustein 3.2 (L.SBN.0083), S.A.S by the DFG (EXC 257), D.S. by the DFG (SFB 618, SFB 665, EXC 257), the Bundesministerium für Bildung und Forschung (BMBF) (BCCN, BFNL) and the Einstein Foundation, M.R.K. by the DFG (SFB 779), C.S.L., R.T., N.T., A.LS. and T.B. by the ANR (ANR-08-MNPS-037-01 - SynGen), Neuron-ERANET (EUHF-AUTISM), Fondation Orange and the Fondation FondaMentale, P.F. by the Bettencourt-Schueller Fondation, R.T., T.B., P.F. by the CNRS Neuroinformatic, E.D.G. by the DFG (SFB 779) and the BMBF (EraNET Neuron), and T.M.B. by the DFG (Bo 1718/3-1 and 1718/4-1; SFB 497/B8).

Author information

Author notes

  1. Ehab Shiban

    Present address: Present address: Klinikum rechts der Isar, Technische Universität München, Neurosurgery Department, Ismaninger Str. 22, 81675 Munich, Germany.,

  2. Michael J. Schmeisser, Elodie Ey and Stephanie Wegener: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Anatomy and Cell Biology, Ulm University, 89081 Ulm, Germany,

    Michael J. Schmeisser, Juergen Bockmann, Angelika Kuebler, Anna-Lena Janssen, Patrick T. Udvardi, Ehab Shiban, Andreas M. Grabrucker & Tobias M. Boeckers

  2. Human Genetics and Cognitive Functions, Institut Pasteur, 75724 Paris CEDEX 15, France,

    Elodie Ey, Claire S. Leblond, Nicolas Torquet, Anne-Marie Le Sourd, Roberto Toro & Thomas Bourgeron

  3. CNRS, URA 2182 ‘Genes, Synapses and Cognition’, Institut Pasteur, 75724 Paris CEDEX 15, France,

    Elodie Ey, Claire S. Leblond, Nicolas Torquet, Anne-Marie Le Sourd, Roberto Toro & Thomas Bourgeron

  4. University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, 75013 Paris, France,

    Elodie Ey, Claire S. Leblond, Nicolas Torquet, Anne-Marie Le Sourd, Roberto Toro & Thomas Bourgeron

  5. Neuroscience Research Center, Cluster of Excellence NeuroCure, Charité, 10117 Berlin, Germany,

    Stephanie Wegener, A. Vanessa Stempel, Sarah A. Shoichet & Dietmar Schmitz

  6. PG Neuroplasticity, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany,

    Christina Spilker & Michael R. Kreutz

  7. Department of Psychology, Laboratory of Biological Psychology, Catholic University of Leuven, 3000 Leuven, Belgium,

    Detlef Balschun

  8. Institute of Experimental Pathology (ZMBE), University of Muenster, 48149 Muenster, Germany,

    Boris V. Skryabin

  9. Interdisciplinary Center for Clinical Research (IZKF), University of Muenster, 48149 Muenster, Germany,

    Boris V. Skryabin

  10. Department of Synaptic Plasticity, Max Planck Institute for Brain Research, 60528 Frankfurt, Germany,

    Susanne tom Dieck

  11. Department of Neurochemistry, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany,

    Karl-Heinz Smalla & Eckart D. Gundelfinger

  12. Neurogenetics Special Laboratory, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany,

    Dirk Montag

  13. University Paris 06, CNRS, UMR 7102, 75005 Paris, France,

    Philippe Faure

Authors
  1. Michael J. Schmeisser
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elodie Ey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephanie Wegener
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juergen Bockmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Vanessa Stempel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Angelika Kuebler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anna-Lena Janssen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Patrick T. Udvardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ehab Shiban
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christina Spilker
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Detlef Balschun
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Boris V. Skryabin
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Susanne tom Dieck
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Karl-Heinz Smalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Dirk Montag
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Claire S. Leblond
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Philippe Faure
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Nicolas Torquet
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Anne-Marie Le Sourd
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Roberto Toro
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Andreas M. Grabrucker
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Sarah A. Shoichet
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Dietmar Schmitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Michael R. Kreutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Thomas Bourgeron
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Eckart D. Gundelfinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Tobias M. Boeckers
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.J.S., E.E., J.B., C.S., D.B., S.t.D., K.H.S., D.M., D.S., M.R.K., T.B., E.D.G. and T.M.B. designed the outline of this study. J.B. and B.V.S. generated, and J.B., C.S. and S.A.S. supervised breeding of, the ProSAP1/Shank2-mutant mice. J.B. supervised breeding of the ProSAP2/Shank3-mutant mice. M.J.S., A.K., A-L.J., P.T.U. and A.M.G. performed all the biochemistry, real-time PCR, Golgi stainings, electron microscopy, transfection of primary neurons and immunohistochemistry, E.E., C.S., D.M., C.S.L., P.F., N.T. and A.LS. the behavioural experiments, and S.W., A.V.S. and D.B. the electrophysiological experiments. E.S. conducted the survival analysis. M.J.S., E.E., S.W., A.V.S., C.S., D.B., D.M., R.T. and A.M.G. performed all data analyses and jointly drafted the manuscript with S.A.S., D.S., M.R.K., T.B., E.D.G. and T.M.B. All authors read and approved the final version. M.J.S., E.E. and S.W. contributed equally to this study. We thank H.-J. Kreienkamp, Hamburg, for providing the pan-Shank antibody ‘189.3’.

Corresponding author

Correspondence to Tobias M. Boeckers.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-15, Supplementary Methods, Supplementary References and Supplementary Tables. (PDF 3097 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Schmeisser, M., Ey, E., Wegener, S. et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486, 256–260 (2012). https://doi.org/10.1038/nature11015

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11015

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

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research