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

Naturevolume 486, pages256–260 (2012)Cite this article

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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 enhancedN-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 onProSAP1/Shank2−/− mutants withProSAP2/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.

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Figure 1:Cyto-architechtural and molecular changes inProSAP1/Shank2−/− mouse brain.
Figure 2:Imbalanced hippocampal glutamatergic synaptic transmission inProSAP1/Shank2−/−mice.
Figure 3:Increased locomotor activity and stereotypical behaviours inProSAP1/Shank2−/− mice.
Figure 4:Abnormalities in social and vocal behaviour ofProSAP1/Shank2−/− mice in the resident–intruder test and during the interaction of a male with an oestrus female.

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  • 13 June 2011

    A present address was added to the affiliations.

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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
  2. Elodie Ey
  3. Stephanie Wegener
  4. Juergen Bockmann
  5. A. Vanessa Stempel
  6. Angelika Kuebler
  7. Anna-Lena Janssen
  8. Patrick T. Udvardi
  9. Ehab Shiban
  10. Christina Spilker
  11. Detlef Balschun
  12. Boris V. Skryabin
  13. Susanne tom Dieck
  14. Karl-Heinz Smalla
  15. Dirk Montag
  16. Claire S. Leblond
  17. Philippe Faure
  18. Nicolas Torquet
  19. Anne-Marie Le Sourd
  20. Roberto Toro
  21. Andreas M. Grabrucker
  22. Sarah A. Shoichet
  23. Dietmar Schmitz
  24. Michael R. Kreutz
  25. Thomas Bourgeron
  26. Eckart D. Gundelfinger
  27. Tobias M. Boeckers

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, theProSAP1/Shank2-mutant mice. J.B. supervised breeding of theProSAP2/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 toTobias M. Boeckers.

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The authors declare no competing financial interests.

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Schmeisser, M., Ey, E., Wegener, S.et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2.Nature486, 256–260 (2012). https://doi.org/10.1038/nature11015

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Editorial Summary

Synapse defects linked to autism

ProSAP/Shank scaffolding proteins are part of the complex protein machinery of the postsynaptic density region at excitatory synapses, and have been genetically linked to some forms of autism. Tobias Boeckers and colleagues generate a Shank2-knockout mouse that is extremely hyperactive, and displays autism-related behaviours such as increased anxiety and abnormal social behaviour. At the cellular level, glutamatergic activity is increased, which is the opposite effect of that seen in mice lacking a related protein, Shank3. These results suggest that balanced levels of individual ProSAP/Shank family members are essential to normal synaptic function, and highlight the fact that opposing cellular and molecular effects can lead to similar behavioural phenotypes. Eunjoon Kim and colleagues demonstrate that Shank2-mutant mice carrying a mutation identical to a microdeletion in the humanSHANK2 gene that is associated with Autism spectrum disorder are hyperactive and exhibit autism-like behaviours, including disrupted social behaviours. The mice have decreased NMDA glutamate-receptor (NMDAR) function, and their social behaviour can be improved by restoring NMDAR function pharmacologically.

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