Letter | Published:

Adult restoration of Shank3 expression rescues selective autistic-like phenotypes

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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , & Autism Spectrum Disorders 1st edn (Oxford Univ. Press, 2011)

  2. 2.

    et al. Novel de novo SHANK3 mutation in autistic patients. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 150B, 421–424 (2009)

  3. 3.

    & State, M. W. The genetics of autism: key issues, recent findings, and clinical implications. Psychiatr. Clin. North Am. 33, 83–105 (2010)

  4. 4.

    et al. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLoS Genet. 10, e1004580 (2014)

  5. 5.

    et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am. J. Hum. Genet. 81, 1289–1297 (2007)

  6. 6.

    et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genet. 39, 25–27 (2007)

  7. 7.

    & Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493, 327–337 (2013)

  8. 8.

    et al. GKAP, a novel synaptic protein that interacts with the guanylate kinase- like domain of the PSD-95/SAP90 family of channel clustering molecules. J. Cell Biol. 136, 669–678 (1997)

  9. 9.

    et al. SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density. J. Biol. Chem. 272, 11943–11951 (1997)

  10. 10.

    et al. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum. Mol. Genet. 20, 3093–3108 (2011)

  11. 11.

    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)

  12. 12.

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

  13. 13.

    et al. Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J. Neurosci. 32, 6525–6541 (2012)

  14. 14.

    & The Shank family of scaffold proteins. J. Cell Sci. 113, 1851–1856 (2000)

  15. 15.

    et al. Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family. Biochem. Biophys. Res. Commun. 264, 247–252 (1999)

  16. 16.

    et al. SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature 503, 72–77 (2013)

  17. 17.

    et al. A directional strategy for monitoring Cre-mediated recombination at the cellular level in the mouse. Nature Biotechnol. 21, 562–565 (2003)

  18. 18.

    et al. Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission. Nature 511, 236–240 (2014)

  19. 19.

    , & A Cre recombinase transgene with mosaic, widespread tamoxifen-inducible action. Genesis 32, 8–18 (2002)

  20. 20.

    et al. Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors. Cell 158, 198–212 (2014)

  21. 21.

    et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448, 894–900 (2007)

  22. 22.

    et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010)

  23. 23.

    et al. Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature 501, 179–184 (2013)

  24. 24.

    et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416, 396–400 (2002)

  25. 25.

    & Motor learning and the cerebellum. Cold Spring Harb. Perspect. Biol. 7, a021683 (2015)

  26. 26.

    & The genotoxicity of tamoxifen: extent and consequences, Kona, Hawaii, January 23, 2003. Mutagenesis 18, 395–399 (2003)

  27. 27.

    , , , & Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007)

  28. 28.

    et al. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 151, 709–723 (2012)

  29. 29.

    , , & A CAAX or a CAAL motif and a second signal are sufficient for plasma-membrane targeting of ras proteins. EMBO J. 10, 4033–4039 (1991)

Download references


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.


  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


  1. Search for Yuan Mei in:

  2. Search for Patricia Monteiro in:

  3. Search for Yang Zhou in:

  4. Search for Jin-Ah Kim in:

  5. Search for Xian Gao in:

  6. Search for Zhanyan Fu in:

  7. Search for Guoping Feng in:


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.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

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

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.