Adult restoration of Shank3 expression rescues selective autistic-like phenotypes
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Author(s)
Mei, Yuan
Monteiro, Patricia
Zhou, Yang
Kim, Jinah
Gao, Xian
Fu, Zhanyan
Feng, Guoping
Date Issued
February 2016
Journal
Nature
Publisher
Nature Publishing Group
Citation
Mei, Yuan et al. “Adult Restoration of Shank3 Expression Rescues Selective Autistic-Like Phenotypes.” Nature 530, 7591 (February 2016): 481–484 © 2016 Macmillan Publishers Limited
Version
Author's final manuscript
Abstract
Because autism spectrum disorders are neurodevelopmental disorders and patients typically display symptoms before the age of three, 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 cases. SHANK3 is a postsynaptic scaffold protein that regulates synaptic development, function and plasticity by orchestrating the assembly of post synaptic density macromolecular signalling complex. Disruptions of the Shank3 gene in mouse models have resulted in synaptic defects and autistic-like behaviours including anxiety, social interaction deficits, and repetitive behaviour. 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.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
McGovern Institute for Brain Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1038/NATURE16971
