Major motor and gait deficits with sexual dimorphism in a Shank3 mutant mouse model

Background Contrasting findings were reported in several animal models with a Shank3 mutation used to induce various autism spectrum disorder (ASD) symptoms. Here, we aimed at investigating behavioral, cellular, and molecular consequences of a C-terminal (frameshift in exon 21) deletion in Shank3 protein in mice, a mutation that is also found in clinical conditions and which results in loss of major isoforms of Shank3. A special focus was made on cerebellar related parameters. Methods All three genotypes were analyzed [wild type (WT), heterozygote (Shank3+/Delta C) and homozygote (Shank3 Delta C/Delta C)] and males and females were separated into two distinct groups. Motor and social behavior, gait, Purkinje cells (PC) and glutamatergic protein levels were determined. Behavioral and cellular procedures used here were previously validated using two environmental animal models of ASD. ANOVA and post-hoc analysis were used for statistical analysis. Results Shank3 Delta C/Delta C mice showed significant impairments in social novelty preference, stereotyped behavior and gait. These were accompanied by a decreased number of PC in restricted cerebellar sub-regions and decreased cerebellar expression of mGluR5. Females Shank3 Delta C/Delta C were less affected by the mutation than males. Shank3+/Delta C mice showed impairments only in social novelty preference, grooming, and decreased mGluR5 expression and that were to a much lesser extent than in Shank3 Delta C/Delta C mice. Limitations As Shank3 mutation is a haploinsufficiency, it is of interest to emphasize that Shank3+/Delta C mice showed only mild to no deficiencies compared to Shank3 Delta C/Delta C. Conclusions Our findings indicate that several behavioral, cellular, and molecular parameters are affected in this animal model. The reported deficits are more pronounced in males than in females. Additionally, male Shank3 Delta C/Delta C mice show more pronounced alterations than Shank3+/Delta C. Together with our previous findings in two environmental animal models of ASD, our studies indicate that gait dysfunction constitutes a robust set of motor ASD symptoms that may be considered for implementation in clinical settings as an early and quantitative diagnosis criteria.

Automated summary

The Shank3 Delta C/Delta C mice exhibited significant impairments in social behavior, stereotyped behavior, and gait, along with decreased Purkinje cells and mGluR5 expression in the cerebellum. On the other hand, Shank3+/Delta C mice only showed impairments in social behavior and reduced mGluR5 expression to a lesser extent. The deficits were more pronounced in male mice compared to females.