Sex differences in microglial developmental gene expression programs

Microglia and the inflammatory cytokines they produce (e.g., in response to injury or infection) are also increasingly implicated in neural dysfunction during development and the risk of neuropsychiatric disorders. Increasing evidence suggests many neurological disorders emerge because of disrupted neuronal developmental trajectory (Marin, 2016). Considering the critical role of microglia for integration of neurons into their proper circuitry as well in proper synapse formation, there is a pressing need to understand the mechanisms underlying normal and abnormal microglia development, their interactions with specific neuronal subsets, and to understand the utility of these same analyses for human tissue. Moreover, as there are pronounced sex differences in the presentation of many neurological disorders, it is critical to understand these mechanisms in both males and females. Here we study developmental gene expression changes in male and female mice from E18 to P60. We isolated microglia from male and female hippocampi of mice from different developmental ages ranging from embryonic day 18 (E18) to postnatal day 60 (P60). Hippocampus was selected based on its importance to mental health, its marked vulnerability relative to other brain regions in response to diverse threats to homeostasis (epilepsy, stroke, and cardiac arrest (Fujioka et al., 2000; Petito, Feldmann, Pulsinelli, & Plum, 1987; Salmenpera, Kalviainen, Partanen, & Pitkanen, 1998; Sapolsky, Uno, Rebert, & Finch, 1990)), and due to evidence of morphological sex differences in microglial development in this region (Schwarz, Sholar, & Bilbo, 2012). It was found that developmental gene expression changes were more advanced in females at P60 and that treatment with LPS, a potent immune activator, could normalize developmental gene expression differences in males.