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
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
Extended data figures
This file contains full blots for all western blots used in the Main and Extended Data Figures.