Oxytocin improves maternal licking behavior deficits in autism-associated Shank3 mutant dogs

Impaired social interaction and repetitive behavior are key features observed in individuals with autism spectrum disorder (ASD). SHANK3 is a high-confidence ASD risk gene that encodes an abundant scaffolding protein in the postsynaptic density. In wild-type (WT) domestic dogs, maternal behaviors such as licking and nursing (largely milk feeding) of puppies are most commonly observed. To address whether SHANK3 plays a role in social behaviors especially maternal behaviors, we analyzed Shank3 mutant dogs generated by CRISPR/Cas9 methodology. We found that Shank3 mutant dams exhibited a fewer and shorter licking behavior, as well as reduced nursing frequency when compared with WT dams. Additionally, a significant decrease in blood oxytocin (OXT) concentration was detected in Shank3 mutant dams. We thus conducted a vehicle-controlled experiment to examine whether a two-week intranasal OXT treatment, initiated on the 8^th postpartum day, could rescue the maternal licking deficits in Shank3 mutant dams. We found that the decreased licking behavior in Shank3 mutant dams was significantly attenuated both acutely and chronically by OXT treatment. The rescue effect of OXT implicates an oxytocinergic contribution to the maternal defects in Shank3 mutant dams, suggesting a potential therapeutic strategy for SHANK3-associated ASD.