Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors

Abstract

Microglia, the innate immune cells of the brain, have recently been removed from the position of mere sentinels and promoted to the role of active sculptors of developing circuits and cells. Alongside their functions in normal brain development, microglia coordinate sexual differentiation of the brain, a set of processes which vary by region and endpoint like that of microglia function itself. In this review, we highlight the ways microglia are both targets and drivers of brain sexual differentiation. We examine the factors that may drive sex differences in microglia, with a special focus on how changing microenvironments in the developing brain dictate microglia phenotypes and discuss how their diverse functions sculpt lasting sex‐specific changes in the brain. Finally, we consider how sex‐specific early life environments contribute to epigenetic programming and lasting sex differences in microglia identity.

Microglial synaptic pruning on axon initial segment of dentate granule cells: sexually dimorphic effects on fear response of adult rats subjected to early life stress

“…In the developing brain, chromosomal sex, gonadal hormone exposure or differential microenvironmental signals might play a role. However, since microglia expression at early postnatal age is very low the most likely mechanism is that prenatal hormone milieu induces differential changes in the microenvironment of males and females and is this different microenvironment the responsible for differences in the activity of microglial activity (VanRyzin, Marquardt et al 2020). For instance, It has been demonstrated that the perinatal surge of testosterone induces an elevated cannabinoid tone in amygdala and this in turn induces a phagocytic ameboid phenotype in male microglia (VanRyzin, Marquardt et al 2019).…”

Physiological sex differences in microglia and their relevance in neurological disorders

“…TLR7 is implicated in miRNA-mediated increased TNFα release, and different expression of Tlr7 in females may contribute to intrinsic differences in immune response [82] . Therefore, male and female microglia are differentially influenced by these factors since early developmental stages [83] .…”

“…Recent work has shown that microglia contribute to sex differences in social behavior [83] and further research will determine to what extent microglia partake in the brain sexual dimorphism. How such intrinsic differences contribute to disease susceptibility also remains to be elucidated [30,39] .…”

Astrocytic Factors Controlling Synaptogenesis: A Team Play

“…For example, in glaucoma, astrocytes have been demonstrated to constitutively perform phagocytosis through internalizations of large portions of axonal cytoplasm and axon-derived organelles [ 85 ]. Interestingly, similarly to microglia [ 86 , 87 ], the phagocytic activity of astrocytes appears to be influenced by sex, as recently demonstrated by the use of synthetic steroids which induce a significantly higher phagocytic activity in astrocytes derived from female mice under resting and inflammatory conditions [ 88 ].…”