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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 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.

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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

    • Michael J. Schmeisser
    • , Elodie Ey
    •  & Stephanie Wegener

    These authors contributed equally to this work.

    • Ehab Shiban

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

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. Laboratory of Biological Psychology, Department of 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. Max Planck Institute for Brain Research, Department of Synaptic Plasticity, 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

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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’.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tobias M. Boeckers.

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https://doi.org/10.1038/nature11015

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