Article | Published:

Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

Nature volume 472, pages 437442 (28 April 2011) | Download Citation

Abstract

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan–McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice.

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Acknowledgements

We thank C. Duarte, S. Chaterjee and A. Oliveira-Maia for discussions; L. Kruger and Q. Liu for technical assistance; A. Hadiono for assistance in behavioural annotation; D. Bredt for the PSD-93 antibody; T. Boeckers for the anti-SHANK3 antibody; S. Miller and P. Christopher for advice and assistance with electron microscopy techniques; J. Crawley for the demonstration of social behaviour tests; N. Calakos and Y. Wan for advice on electrophysiology studies; A. Graybiel for critical comments of the manuscript; D. Wang and the other members of the G.F. laboratory for their support. We thank The Poitras Center for Affective Disorders Research. This work was funded by a grant from NIMH/NIH (R01MH081201), a Hartwell Individual Biomedical Research Award from The Hartwell Foundation, and a Simons Foundation Autism Research Initiative (SFARI) grant Award to G.F.; a NARSAD Young Investigator Award and NIH Ruth L. Kirschstein National Research Service Award (F32MH084460) to J.T.T.; a NIH (R03MH085224) grant to Z.F.; and doctoral fellowships from the Portuguese Foundation for Science and Technology to J.P. (SFRH/BD/15231/2004) and C.F. (SFRH/BD/15855/2005). C.F. would like to acknowledge the support from the “Programa Gulbenkian de Doutoramento em Biomedicina” (PGDB, Oeiras, Portugal) and J.P. the “Programa Doutoral em Biologia Experimental e Biomedicina” (CNC, Coimbra, Portugal).

Author information

Author notes

    • João Peça
    •  & Cátia Feliciano

    These authors contributed equally to this work.

Affiliations

  1. Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA

    • João Peça
    • , Cátia Feliciano
    • , Jonathan T. Ting
    • , Wenting Wang
    • , Michael F. Wells
    • , Christopher D. Lascola
    • , Zhanyan Fu
    •  & Guoping Feng
  2. PhD Programme in Biomedicine and Experimental Biology (BEB), Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    • João Peça
  3. Gulbenkian PhD Programme in Biomedicine, Gulbenkian Science Institute, 2781-901 Oeiras, Portugal

    • Cátia Feliciano
  4. Department of Radiology, and Brain Imaging and Analysis Center, Duke University Medical Center, Durham, North Carolina 27710, USA

    • Talaignair N. Venkatraman
    •  & Christopher D. Lascola
  5. Department of Psychiatry and Behavioral Science, Duke University Medical Center, Durham, North Carolina 27710, USA

    • Zhanyan Fu
  6. McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Zhanyan Fu
    •  & Guoping Feng
  7. Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts 02142, USA

    • Guoping Feng

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Contributions

J.P., C.F., J.T.T., W.W., M.F.W., T.N.V., C.D.L. and Z.F. participated in the execution and analysis of experiments. J.P., C.F., J.T.T., C.D.L, Z.F. and G.F participated in the interpretation of the results. J.P., C.F. and G.F. designed the experiments and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Guoping Feng.

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    Supplementary Information

    The file contains Supplementary Figures 1-15 with legends and Supplementary Tables 1-2.

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DOI

https://doi.org/10.1038/nature09965

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