Sex differences in microglial activation in the developing rat brain

Abstract

During development, microglial progenitor cells migrate and infiltrate into the brain from the periphery: a process critical to the maturation of the developing brain. Immature microglia are distinct from adult microglia, as they produce elevated levels of cytokines compared to ramified, adult microglia. These immature microglia are often classified as “activated.” But, further activation of immature microglia, via immune activation, can lead to long-term neuronal and cognitive dysfunction. Microglial activation is associated with multiple neuro developmental disorders including autism, ADHD, schizophrenia, and cerebral palsy – disorders with suspected immune etiologies, and strong sex biases for males. Still, the interactions between immature microglia and other neural cells, leading to these outcomes, are understudied. It has previously been shown that female rats do not show the same long-term behavioral deficits that male rats show following infection at P4 (Bilbo et al., 2012). We hypothesized that male rat pups would be more vulnerable to an immune challenge during microglial infiltration and maturation. We exposed primary, sex-specific, microglial cells from the hippocampus of rat pups to lipopolysaccharide on P4, in the presence or absence of other neural cells. Mixed and microglial cultures were analyzed for inflammatory gene expression to determine whether immature microglial cells exhibited a sex-specific response to immune activation, and if the presence of all other neural cells influenced that response. Funding source: NIH R21MH104280 and R01MH106553.