Sex-specific modulation of anxiety-like behavior by forebrain neuronal SMC3 in mice

SMC3 is a chromatin binding factor that plays central roles in genome organization and in proper neurodevelopment. Mutations in SMC3 gene (SMC3) induce neurodevelopmental and behavioral phenotypes in humans, including changes in anxiety behavior and self-injury. However, it is not clear what are the exact roles of SMC3 in behavior in adulthood or if its effects are only developmental. Using an adult forebrain excitatory neuron specific Smc3 knockout mouse model, the current study determined specific sex-dependent effects of SMC3 ablation during adulthood. Behavioral tests identified anxiolytic effects of Smc3 knockout in females and anxiogenic effects in males four weeks after initiation of adult knockout. The prefrontal cortex, a regulator of anxiety behavior, also displayed sex-dependent effects in dendritic branching. Transcriptional analysis revealed gene expression effects of Smc3 knockout in males and females, including changes in anxiety-related genes and relevant transcriptional pathways. While effects on anxiety behavior was sex-specific, both males and females developed self-injury behavior at approximately ten weeks after induction of knockout. The current study suggests that neuronal SMC3 modulates anxiety during adulthood in a sex-specific manner.