Gonadal hormones impart male-biased behavioral vulnerabilities to immune activation via microglial mitochondrial function

There is a strong male bias in the prevalence of many neurodevelopmental disorders such as autism spectrum disorder. However, the mechanisms underlying this sex bias remain elusive. Infection during the perinatal period is associated with an increased risk of neurodevelopmental disorder development. Here, we used a mouse model of early-life immune activation that reliably induces deficits in social behaviors only in males. We demonstrate that male-biased alterations in social behavior are dependent upon microglial immune signaling and are coupled to alterations in mitochondrial morphology, gene expression, and function specifically within microglia, the innate immune cells of the brain. Additionally, we show that this behavioral and microglial mitochondrial vulnerability to early-life immune activation is programmed by the male-typical perinatal gonadal hormone surge. These findings demonstrate that social behavior in males over the lifespan are regulated by microglia-specific mechanisms that are shaped by events that occur in early development.

Automated summary

There is a strong male bias in many neurodevelopmental disorders such as autism spectrum disorder, but the mechanisms behind this bias are unknown. Infection during the perinatal period increases the risk of neurodevelopmental disorders. Using a mouse model, researchers found that early-life immune activation only induced deficits in social behaviors in male mice. These behavioral changes were associated with alterations in microglial immune signaling, mitochondrial morphology, gene expression, and function specifically in microglia, the brain's innate immune cells. Furthermore, the vulnerability to early-life immune activation and its effects on behavior and microglial mitochondria were programmed by the male-typical perinatal gonadal hormone surge. These findings highlight the role of microglia-specific mechanisms shaped by early developmental events in regulating male social behavior throughout lifespan.