IRF8 deficiency causes anxiety-like behavior with sex differences

Anxiety disorder is a serious psychiatric disease that affects women more than men and disrupts patients' daily lives. It is often comorbid with major depression and other mental diseases. Various underlying mechanisms have been proposed, such as neurotransmitters and neuroanatomical disruptions, and more recently, oxidative stress; however, much remains unclear, including the role of glial cells. Here, we investigated the role of IRF8 in anxiety-like behavior using mouse models. IRF8 is a transcription factor expressed primarily in microglia in the brain. A battery of behavioral tests revealed that female IRF8 knockout (IRF8KO) mice show increased anxiety-like behavior relative to male IRF8KO and wild-type mice. Female IRF8KO mice also exhibited a higher tendency for obsessive-compulsive-like disorder. However, these behavioral abnormalities were not observed when IRF8 was deleted postnatally, indicating that it acts during the fetal stage to control anxiety-like behavior. Transcriptome analysis revealed that IRF8 deficiency leads to redox dysregulation. Further, 2',7'-dichlorofluorescin diacetate (DCFDA) staining for microglia demonstrated that female IRF8KO microglia produce higher levels of reactive oxygen species (ROS) compared to WT and male IRF8KO counterparts. Detailed RNA-seq analysis, however, did not reveal specific genes that cause high ROS production in female cells. In sum, this work demonstrates that IRF8 in microglia plays a major role in controlling anxiety and OCD-like behavior with potential sex-specific differences.