Early restoration of shank3 expression in Shank3 knock-out mice prevents core asd-like behavioral phenotypes
Several genes are associated with increased risk for autism spectrum disorder (ASD), neurodevelopmental disorders that present with repetitive movements and restricted interests along with deficits in social interaction/communication. While genetic alterations associated with ASD are present early in life, ASD-like behaviors are difficult to detect in early infancy. This raises the issue of whether reversal of an ASD-associated genetic alteration early in life can prevent the onset of ASD-like behaviors. Genetic alterations of SHANK3, a well-characterized gene encoding a postsynaptic scaffolding protein, are estimated to contribute to ∼0.5% of ASD and remain one of the more replicated and well-characterized genetic defects in ASD. Here, we investigate whether early genetic reversal of a Shank3 mutation can prevent the onset of ASD-like behaviors in a mouse model. Previously, we have demonstrated that mice deficient in Shank3 display a wide range of behavioral abnormalities such as repetitive grooming, social deficits, anxiety, and motor abnormalities. In this study, we replicate many of these behaviors in Shank3 mutant mice. With early genetic restoration of wild-type (WT) Shank3, we rescue behaviors including repetitive grooming and social, locomotor, and rearing deficits. Our findings support the idea that the underlying mechanisms involving ASD behaviors in mice deficient in Shank3 are susceptible to early genetic correction of Shank3 mutations.
Keywords: Phelan–McDermid syndrome; Shank3; autism; autism spectrum disorder; behavior; genetic reversal.
Biology and Biomarkers