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

Nature volume 486, pages 261–265 (2012)Cite this article

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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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Figure 1: Shank2 −/− mice exhibit ASD-like impaired social interaction and social communication, and repetitive jumping.
Figure 2: Impaired NMDAR-dependent synaptic plasticity in Shank2 −/− mice.
Figure 3: d -cycloserine normalizes NMDAR function and improves social interaction in Shank2 −/− mice.
Figure 4: CDPPB normalizes NMDAR function and substantially improves social interaction in Shank2 −/− mice.

References

  1. 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 

  2. Sheng, M. & Kim, E. The shank family of scaffold proteins. J. Cell Sci. 113, 1851–1856 (2000)

    CAS  PubMed  Google Scholar 

  3. Boeckers, T. M., Bockmann, J., Kreutz, M. R. & Gundelfinger, E. D. ProSAP/Shank proteins—a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease. J. Neurochem. 81, 903–910 (2002)

    Article  CAS  Google Scholar 

  4. Ehlers, M. D. Synapse structure: glutamate receptors connected by the shanks. Curr. Biol. 9, R848–R850 (1999)

    Article  CAS  Google Scholar 

  5. 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 

  6. Ehninger, D. & Silva, A. J. Rapamycin for treating tuberous sclerosis and autism spectrum disorders. Trends Mol. Med. 17, 78–87 (2011)

    Article  CAS  Google Scholar 

  7. Ramocki, M. B. & Zoghbi, H. Y. Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455, 912–918 (2008)

    Article  ADS  CAS  Google Scholar 

  8. Jamain, S. et al. Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc. Natl Acad. Sci. USA 105, 1710–1715 (2008)

    Article  ADS  CAS  Google Scholar 

  9. 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 

  10. 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 

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

    Article  ADS  Google Scholar 

  12. 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 

  13. 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 

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

    Article  CAS  Google Scholar 

  15. Südhof, T. C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911 (2008)

    Article  ADS  Google Scholar 

  16. 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 

  17. Gregory, K. J., Dong, E. N., Meiler, J. & Conn, P. J. Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential. Neuropharmacology 60, 66–81 (2011)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Hayashi, M. K. et al. The postsynaptic density proteins Homer and Shank form a polymeric network structure. Cell 137, 159–171 (2009)

    Article  CAS  Google Scholar 

  20. Oliet, S. H., Malenka, R. C. & Nicoll, R. A. Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells. Neuron 18, 969–982 (1997)

    Article  CAS  Google Scholar 

  21. Zhu, J. J., Qin, Y., Zhao, M., Van Aelst, L. & Malinow, R. Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110, 443–455 (2002)

    Article  CAS  Google Scholar 

  22. Shepherd, J. D. & Huganir, R. L. The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu. Rev. Cell Dev. Biol. 23, 613–643 (2007)

    Article  CAS  Google Scholar 

  23. Blundell, J. et al. Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J. Neurosci. 30, 2115–2129 (2010)

    Article  CAS  Google Scholar 

  24. Uslaner, J. M. et al. Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus. Neuropharmacology 57, 531–538 (2009)

    Article  CAS  Google Scholar 

  25. Verpelli, C. et al. Importance of Shank3 protein in regulating metabotropic glutamate receptor 5 (mGluR5) expression and signaling at synapses. J. Biol. Chem. 286, 34839–34850 (2011)

    Article  CAS  Google Scholar 

  26. Kinney, G. G. et al. A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. J. Pharmacol. Exp. Ther. 313, 199–206 (2005)

    Article  CAS  Google Scholar 

  27. Ayala, J. E. et al. mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology 34, 2057–2071 (2009)

    Article  CAS  Google Scholar 

  28. Auerbach, B. D., Osterweil, E. K. & Bear, M. F. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63–68 (2011)

    Article  ADS  CAS  Google Scholar 

  29. Darrah, J. M., Stefani, M. R. & Moghaddam, B. Interaction of N-methyl-d-aspartate and group 5 metabotropic glutamate receptors on behavioral flexibility using a novel operant set-shift paradigm. Behav. Pharmacol. 19, 225–234 (2008)

    Article  CAS  Google Scholar 

  30. Schmeisser, M. J. et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature http://dx.doi.org/10.1038/nature11015 (29 April 2012)

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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.

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Author notes

  1. Hyejung Won, Hye-Ryeon Lee, Heon Yung Gee, Won Mah and Jae-Ick Kim: These authors contributed equally to this work.

Authors and Affiliations

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

    Hyejung Won, Won Mah, Jiseok Lee, Seungmin Ha, Changuk Chung & Eunjoon Kim

  3. Department of Biological Sciences, National Creative Research Initiative Center for Memory, 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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  1. Hyejung Won
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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.

Corresponding authors

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

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-21 and Supplementary Methods with additional references. (PDF 17263 kb)

Supplementary Table 1

This table contains the information on the number, gender and age of animals used in the experiments associated with this paper. (XLS 45 kb)

Supplementary Table 2

This table contains the statistical results of the experiments associated with this paper. (XLS 118 kb)

Supplementary Movie 1

This movie shows a pup retrieval assay with a wild-type mouse. (MOV 12752 kb)

Supplementary Movie 2

This movie shows a pup retrieval assay with a Shank2−/− mouse. (MOV 25132 kb)

Supplementary Movie 3

This movie shows an example of repetitive jumping mixed with upright scrabbling in a Shank2−/− mouse. (MOV 1584 kb)

Supplementary Movie 4

This movie shows an example of repetitive grooming in a Shank2−/− mouse. (MOV 1103 kb)

Supplementary Movie 5

This movie shows an example of repetitive digging in a Shank2−/− mouse. (MOV 1975 kb)

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Won, H., Lee, HR., Gee, H. et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486, 261–265 (2012). https://doi.org/10.1038/nature11208

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