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Sex differences in microglial phagocytosis in the neonatal hippocampus.

ABSTRACT: Microglia regulate brain development through many processes, such as promoting neurogenesis, supporting cell survival, and phagocytizing progenitor, newly-born, and dying cells. Many of these same developmental processes show robust sex differences, yet very few studies have assessed sex differences in microglia function during development. Hormonally-induced sexual differentiation of the brain occurs during the perinatal period, thus we examined sex differences in microglial morphology, phagocytosis, and proliferation in the hippocampus during the early postnatal period. We found that the neonatal female hippocampus had significantly more microglia with phagocytic cups than the male hippocampus. We subsequently found that female microglia phagocytized more neural progenitor cells and healthy cells compared to males, but there were no sex differences in the number of newly-born or dying cells targeted by microglial phagocytosis. We found that the number of phagocytic microglia in females was reduced to male-typical levels by treatment with estradiol, the hormone responsible for masculinizing the rodent brain. Females also had higher expression of several phagocytic pathway genes in the hippocampus compared to males. In contrast to robust sex differences in phagocytic microglia, we found no sex differences in the number of microglia with amoeboid, transitioning, or ramified morphologies or differences in three-dimensional reconstructions of microglial morphology. While we did not find a baseline sex difference in microglial proliferation during or following the prenatal gonadal hormone surge in males, we found that estradiol treatment increased microglia proliferation in females. Overall, these data show that there are important sex differences in microglia function in the hippocampus during the early neonatal period.

SUBMITTER: Nelson LH

PROVIDER: S-EPMC5512447 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Sex differences in microglial phagocytosis in the neonatal hippocampus.

Nelson Lars H LH Warden Spencer S Lenz Kathryn M KM

Brain, behavior, and immunity 20170322

Microglia regulate brain development through many processes, such as promoting neurogenesis, supporting cell survival, and phagocytizing progenitor, newly-born, and dying cells. Many of these same developmental processes show robust sex differences, yet very few studies have assessed sex differences in microglia function during development. Hormonally-induced sexual differentiation of the brain occurs during the perinatal period, thus we examined sex differences in microglial morphology, phagocy ...[more]

PMID: 28341582

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Project description:During normal neurodevelopment, microglia perform a range of different functions that are crucial for the proper development, circuit integration, and function of neurons. These functions include certain types of synaptic pruning during critical stages of neurodevelopment (Schafer et al., 2012), and the production of cytokines and chemokines during normal physiological tasks, proteins which are important for homeostasis in addition to immune defense (Avital et al., 2003; Goshen et al., 2007). 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.

Dataset Information

Sex differences in microglial phagocytosis in the neonatal hippocampus.

Publications

Sex differences in microglial phagocytosis in the neonatal hippocampus.

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