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 adulthood forebrain excitatory neuron specific Smc3 knockout mouse model, the current study determined specific sex-dependent effects of SMC3 ablation during the adulthood. Behavioral tests identified anxiolytic effects of Smc3 knockout in females and anxiogenic effects in males four weeks after initiation of adulthood knockout. The prefrontal cortex, a regulator of anxiety behavior, also displayed sex-dependent effects in dendritic complexity. Transcriptional analysis revealed differential effects of Smc3 knockout in males and females, including changes in anxiety-related genes and relevant transcriptional pathways. While anxiety behavior was sex-specific, both males and females developed self-injury behavior at approximately ten weeks after induction of knockout. The current study demonstrates that neuronal SMC3 regulates anxiety during the adulthood in a sex-specific manner. Overall design: To understand the function of SMC3 in the adulthood brain, we established a neuron-specific knockout of Smc3 specifically in adulthood in mice. Mice with floxed Smc3 and Camk2a-cre/ERT2+ (Cre+) or Camk2a-cre/ERT2- (Cre-). Mice with Cre+ named as cKO due the lack of Smc3 gene after tamoxifen treatment; mice with Cre- served as WT.