Letter | Published:

Adult restoration of Shank3 expression rescues selective autistic-like phenotypes

Nature volume 530, pages 481484 (25 February 2016) | Download Citation

Abstract

Because autism spectrum disorders are neurodevelopmental disorders and patients typically display symptoms before the age of three1, one of the key questions in autism research is whether the pathology is reversible in adults. Here we investigate the developmental requirement of Shank3 in mice, a prominent monogenic autism gene that is estimated to contribute to approximately 1% of all autism spectrum disorder cases2,3,4,5,6. SHANK3 is a postsynaptic scaffold protein that regulates synaptic development, function and plasticity by orchestrating the assembly of postsynaptic density macromolecular signalling complex7,8,9. Disruptions of the Shank3 gene in mouse models have resulted in synaptic defects and autistic-like behaviours including anxiety, social interaction deficits, and repetitive behaviour10,11,12,13. We generated a novel Shank3 conditional knock-in mouse model, and show that re-expression of the Shank3 gene in adult mice led to improvements in synaptic protein composition, spine density and neural function in the striatum. We also provide behavioural evidence that certain behavioural abnormalities including social interaction deficit and repetitive grooming behaviour could be rescued, while anxiety and motor coordination deficit could not be recovered in adulthood. Together, these results reveal the profound effect of post-developmental activation of Shank3 expression on neural function, and demonstrate a certain degree of continued plasticity in the adult diseased brain.

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Acknowledgements

We thank T. Dalia, A. Lim, S. Feng, K. Han, W. Stockton, H. Zaniewski and B. Clear for technical support. We thank Q. Zhang for designing the pAAV-hSYN1-EGFP-P2A-EGFPf-WPRE-HGHpA construct. We thank all members of the Feng laboratory for their support and discussions. Y.M. would like to thank T. Littleton, Y. Lin and K. Tye. P.M. would like to thank C. Duarte and the late S. Chaterjee, and acknowledge support from the ‘Programa Doutoral em Biologia Experimental e Biomedicina’ (CNC, Coimbra, Portugal). This work was funded by the National Science Foundation Graduate Fellowship and Integrative Neuronal Systems to Y.M.; the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard and a doctoral fellowship from the Portuguese Foundation for Science and Technology to P.M. (SFRH/BD/33894/2009). Y.Z. is supported by postdoc fellowships from the Simons Center for the Social Brain at MIT, Nancy Lurie Marks Family Foundation and Shenzhen Overseas Innovation Team Project (no. KQTD20140630180249366). X.G. was supported by the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard and a graduate fellowship from China Scholarship Council. Z.F. is supported by Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard and NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. Research in the Feng laboratory is supported by the Poitras Center for Affective Disorders Research at MIT, Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard, National Institute of Health (NIMH R01MH097104), Nancy Lurie Marks Family Foundation, Simons Foundation Autism Research Initiative (SFARI) and Simons Center for the Social Brain at MIT.

Author information

Author notes

    • Yuan Mei
    •  & Patricia Monteiro

    These authors contributed equally to this work.

Affiliations

  1. McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Yuan Mei
    • , Patricia Monteiro
    • , Yang Zhou
    • , Jin-Ah Kim
    • , Xian Gao
    • , Zhanyan Fu
    •  & Guoping Feng
  2. PhD Programme in Experimental Biology and Biomedicine (PDBEB), Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal

    • Patricia Monteiro
  3. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Masaschusetts 02142, USA

    • Patricia Monteiro
    • , Zhanyan Fu
    •  & Guoping Feng
  4. Key Laboratory of Brain Functional Genomics (Ministry of Education & Science and Technology Commission of Shanghai Municipality), Institute of Cognitive Neuroscience, School of Psychology and Cognitve Science, East China Normal University, Shanghai 200062, China

    • Xian Gao

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Contributions

Y.M., P.M. and G.F. designed the experiments and wrote the paper. Y.M., P.M., Y.Z., J.-A.K., X.G. and Z.F. performed the experiments and analysed the data. Y.M., P.M., Y.Z., J.-A.K., X.G. and Z.F. interpreted the results.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Guoping Feng.

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    Supplementary Information

    This file contains full blots for all western blots used in the Main and Extended Data Figures.

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DOI

https://doi.org/10.1038/nature16971

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