Because autism is a neurodevelopmental disorder with symptom onset before the age of three, one of the key questions in autism research is whether the pathology is reversible in adulthood. Here we investigate the developmental requirement of Shank3, one of the most prevalent genes in monogenic autism. Shank3 encodes a postsynaptic scaffold protein that regulates synaptic development, function and plasticity by orchestrating the assembly of postsynaptic density macromolecular signaling complex. Disruptions of the Shank3 gene in mouse models have resulted in synaptic defects and autistic-like behaviors including anxiety, social interaction deficits, and repetitive/stereotyped behavior. Here we have generated a novel Shank3 conditional knock-in mouse model and used it to demonstrate that re-expression of the Shank3 gene in adult leads to improvement in the synaptic protein composition, dendritic spine density, and neurotransmission in the striatum. We also provide evidence that certain behavioral abnormalities are selectively rescued while other behavioral aspects are not affected.  Together, these results illuminate the profound impact of post-developmental activation of the Shank3 expression on neural function and demonstrate a certain degree of continued plasticity in the diseased brain.