The Disc1 deletion common to many inbred mouse strains has negligible effects on social behavior of 129S4 mice in a semi-natural environment

Numerous mouse models have been engineered to carry alterations to the Disrupted in Schizophrenia 1 (Disc1) gene, thought to be involved in neurodevelopmental conditions. However, most Swiss and probably all 129 mouse substrains, which are widely used in biological research, naturally carry a 25 bp deletion in Disc1 exon 6. Despite the prevalence of these strains, little has been done to characterize the extent to which this natural mutation affects behavioral output and may unintentionally impact studies. Here, we report on experiments to test the effects of this deletion on social and exploratory behaviors. To model natural conditions, we designed a seminatural environment to house groups of mice (4 females and 1 male; 3 groups per strain) for prolonged periods and then employed this model to study social behaviors. First, we compared behavioral phenotypes in C57Bl/6Jrj (B6) mice and 129S4 (S4Disc1-/-) natural mutants to validate our setup. Then, to assess the contribution of the naturally mutated Disc1 to social behavior differences, the wild-type (WT) Disc1 allele was crossed into S4 mice (S4Disc1+/+). S4 and B6 lines were drastically different, with S4 mice being hypoactive, less explorative, and less social than B6 mice. However, S4 mice expressing WT Disc1 only marginally differed from S4Disc1-/- mice, showing little to no contribution of Disc1 to their behavioral phenotype. Thus, this mutation holds little significance for natural exploratory and social behaviors in the seminatural environment.