Adult restoration of Shank3 expression rescues selective autistic-like phenotypes

Re-expression of the Shank3 gene in adult mice results in improvements in synaptic protein composition and spine density in the striatum; Shank3 also rescues autism-like features such as social interaction and grooming behaviour, and the results suggest that aspects of autism spectrum disorders may be reversible in adulthood. Autism-like signs reversed by Shank3 Mutations in the Shank3 gene have been linked to autism, and mice lacking Shank3 expression display features of autism, including social deficits, anxiety and repetitive behaviour, as well as defects in striatal synapses. Guoping Feng and colleagues now show that re-expression of Shank3 in adult mice reversed the synaptic changes and increased spine density in the striatum. It also selectively rescued social interaction and grooming behaviour — two core features of autism — whereas anxiety and motor impairments could only be prevented by Shank3 re-expression during development. These findings show that Shank3 expression can affect neural function post-development, and suggest that aspects of autism spectrum disorder pathology may be reversible in adulthood. Because autism spectrum disorders are neurodevelopmental disorders and patients typically display symptoms before the age of three 1 , 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 2 , 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 complex 7 , 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 behaviour 10 , 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 e