Mutations in SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) are associated with several neurodevelopmental disorders, but it is not known whether correcting SHANK3 levels in the mature CNS would alleviate synaptic impairments in rodents carrying Shank3 mutations. Mei et al. generated a mouse, lacking constitutive expression of Shank3, in which the gene could be conditionally knocked-in at specific time points. Knock-in of Shank3 in these mice during adulthood restored levels of synaptic proteins and corrected physiological impairments in striatal neurons, and rescued impairments in social behaviour. In a different approach, Bidinosti et al. characterized the dysregulation of phosphoprotein expression that occurs in rat cortical neurons that lack Shank3 and showed that the expression of CDC-like kinase 2 (CLK2) was upregulated in these cells. Pharmacological inhibition of CLK2 corrected synaptic deficits in brain slices from adult mice carrying a mutation in exon 21 of Shank3 and rescued impairments in social behaviour in these mice. Together, these findings suggest that adulthood restoration of SHANK3 levels, or restoration of downstream mediators, may be a useful strategy to alleviate some of the synaptic and behavioural impairments associated with SHANK3 mutations.