Adult restoration ofShank3expression rescues selective autistic-like phenotypes

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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 ofShank3in mice, a prominent monogenic autism gene that is estimated to contribute to approximately 1% of all autism spectrum disorder cases2-6. SHANK3 is a postsynaptic scaffold protein that regulates synaptic development, function and plasticity by orchestrating the assembly of postsynaptic density macromolecular signalling complex7-9. Disruptions of theShank3gene in mouse models have resulted in synaptic defects and autistic-like behaviours including anxiety, social interaction deficits, and repetitive behaviour10-13. We generated a novelShank3conditional knock-in mouse model, and show that re-expression of theShank3gene 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 ofShank3expression on neural function, and demonstrate a certain degree of continued plasticity in the adult diseased brain.

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