Letter | Published:

Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function

Nature volume 486, pages 261265 (14 June 2012) | Download Citation

Abstract

Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants1. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses2,3,4, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disablility5. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics6,7,8,9,10,11,12,13,14,15,16, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2−/−) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-d-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with d-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2−/− mice. Furthermore, treatment of Shank2−/− mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation17, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2−/− mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.

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Acknowledgements

We would like to thank Macrogen for assistance in the production of mice. This work was supported by the National Creative Research Initiative Program, WCU program (R31-2008-000-10071-0), and Institute for Basic Science (to E.K.), the National Research Foundation of Korea (to M.G.L.; grant 2012-0000812), the National Creative Research Initiative Program & WCU program (to B.-K.K.; 2007-0054846), the Basic Science Research Program through the National Research Foundation of Korea (to K.L. and Y.C.B.; 2011-0028240), and the National Leading Research Laboratory Program (to D.K.; 2011-0028772). H.-R.L. and J.-I.K. are supported by the BK21 fellowship, and H.W. is supported by the TJ Park Doctoral Fellowship and National Junior Research Fellowship.

Author information

Author notes

    • Hyejung Won
    • , Hye-Ryeon Lee
    • , Heon Yung Gee
    • , Won Mah
    •  & Jae-Ick Kim

    These authors contributed equally to this work.

Affiliations

  1. Department of Biological Sciences, KAIST, Daejeon 305-701, Korea

    • Hyejung Won
    • , Won Mah
    • , Jiseok Lee
    • , Seungmin Ha
    • , Changuk Chung
    • , Sae-Geun Park
    • , Daesoo Kim
    •  & Eunjoon Kim
  2. National Creative Research Initiative Center for Synaptogenesis, KAIST, Daejeon 305-701, Korea

    • Hyejung Won
    • , Won Mah
    • , Jiseok Lee
    • , Seungmin Ha
    • , Changuk Chung
    •  & Eunjoon Kim
  3. National Creative Research Initiative Center for Memory, Department of Biological Sciences, College of Natural Sciences, Seoul National University, Gwanangno 599, Gwanak-gu, Seoul 151-747, Korea

    • Hye-Ryeon Lee
    • , Jae-Ick Kim
    •  & Bong-Kiun Kaang
  4. Department of Pharmacology, Brain Korea 21 Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea

    • Heon Yung Gee
    • , Eun Suk Jung
    • , Jung-Soo Lee
    •  & Min Goo Lee
  5. Department of Oral Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 700-412, Korea

    • Yi Sul Cho
    •  & Yong Chul Bae
  6. Department of Anatomy, School of Medicine, Brain Science & Engineering Institute, Kyungpook National University, Daegu 700-412, Korea

    • Kyungmin Lee
  7. Department of Brain and Cognitive Sciences, Seoul National University, Seoul 151-747, Korea

    • Bong-Kiun Kaang
  8. Graduate School of Nanoscience and Technology (World Class University), KAIST, Daejeon 305-701, Korea

    • Eunjoon Kim
  9. Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 305-811, Korea

    • Eunjoon Kim

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Contributions

H.-R.L., J.-I.K. and B.-K.K. performed and analysed all the electrophysiological experiments and data; H.Y.G., E.S.J. and J.-S.L. generated and characterized Shank2−/− mice; S.-G.P. performed USV experiments; H.W., W.M. and J.L. performed immunoblot analysis; H.W., W.M., S.H. and C.C. contributed to mouse breeding and behavioural characterization; Y.S.C. performed electron microscopy experiments; H.W. and W.M. conducted all the other experiments; K.L., D.K., Y.C.B., B.-K.K., M.G.L. and E.K. supervised the project and wrote the manuscript. B.-K.K., M.G.L. and E.K. contributed equally to this work.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Bong-Kiun Kaang or Min Goo Lee or Eunjoon Kim.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-21 and Supplementary Methods with additional references.

Excel files

  1. 1.

    Supplementary Table 1

    This table contains the information on the number, gender and age of animals used in the experiments associated with this paper.

  2. 2.

    Supplementary Table 2

    This table contains the statistical results of the experiments associated with this paper.

Videos

  1. 1.

    Supplementary Movie 1

    This movie shows a pup retrieval assay with a wild-type mouse.

  2. 2.

    Supplementary Movie 2

    This movie shows a pup retrieval assay with a Shank2−/− mouse.

  3. 3.

    Supplementary Movie 3

    This movie shows an example of repetitive jumping mixed with upright scrabbling in a Shank2−/− mouse.

  4. 4.

    Supplementary Movie 4

    This movie shows an example of repetitive grooming in a Shank2−/− mouse.

  5. 5.

    Supplementary Movie 5

    This movie shows an example of repetitive digging in a Shank2−/− mouse.

About this article

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DOI

https://doi.org/10.1038/nature11208

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