Microglia Display Distinct Sex‐dependent Gene Expression Profiles in The Postnatal and Adult CNS

Abstract

Microglial activation is associated with all CNS disorders, many of which are sexually dimorphic or age‐dependent. However, little is known about whether microglia are sexually dimorphic, or how their basal gene expression is altered with age in the healthy CNS. Analysis of microglia from the brains of 3 day‐ to 12 month‐old male and female C57Bl/6 mice revealed distinct gene expression profiles during postnatal development that are significantly different from adulthood. In addition, we found a 2‐fold higher density of microglia/mg tissue in the postnatal brain than in the adult brain. Postnatal microglia are characterized by high iNOS, TNFα and arginase‐1 mRNA levels, whereas adult microglia (2–4 months) are characterized by low pro‐inflammatory cytokine expression that was increased at 12 months of age. Although the microglial phenotype appears to change with age, microglia in the healthy brain were not committed to an M1 or M2 phenotype at any time. We found sexual dimorphisms in microglia in the absence of sex differences in estrogen receptor expression, and only at P3 when females had higher expression of inflammatory cytokines than males. Since basal gene expression may prime microglial responsiveness to physiological or pathological events, the same stimulus may induce different sex‐and age‐dependent microglial activities, and thereby contribute to altered CNS vulnerability at specific ages.