A starring role for microglia in brain sex differences

Abstract

Microglia, the resident innate immune cells in the brain, have long been understood to be crucial to maintenance in the nervous system, by clearing debris, monitoring for infiltration of infectious agents, and mediating the brain's inflammatory and repair response to traumatic injury, stroke, or neurodegeneration. A wave of new research has shown that microglia are also active players in many basic processes in the healthy brain, including cell proliferation, synaptic connectivity, and physiology. Microglia, both in their capacity as phagocytic cells and via secretion of many neuroactive molecules, including cytokines and growth factors, play a central role in early brain development, including sexual differentiation of the brain. In this review, we present the vast roles microglia play in normal brain development and how perturbations in the normal neuroimmune environment during development may contribute to the etiology of brain-based disorders. There are notable differences between microglia and neuroimmune signaling in the male and female brain throughout the life span, and these differences may contribute to the vast differences in the incidence of neuropsychiatric and neurological disorders between males and females.

Keywords: cytokine; development; hormone; immune; inflammation; microglia; sex; sex differences.

Figure 1

(A) Microglial cells are derived from the embryonic yolk sac from myeloid progenitors that are generated prior to the initiation of hematopoiesis in the fetal liver. These progenitors migrate to the developing brain, colonize and differentiate into microglia, which is a long-lived self-sustaining population of the cells in the brain throughout life. (B). There is a sex bias in the number of microglia in the developing rodent brain, with males having more than females across the neonatal period. It is currently unknown whether more microglia progenitors are recruited into the male brain early in life, whether more proliferation occurs, or whether more cells survive in males than females (or some combination thereof).

Figure 2

Microglia have been implicated as players in many normal developmental processes in the brain, including cell proliferation, survival, apoptosis, and synaptic patterning. Virtually all of these processes show prominent sex differences, thus the sex difference in microglia in the developing brain may contribute to each of these processes.

Figure 3

Microglia contribute to sexual differentiation of the preoptic area (POA) via release of the proinflammatory molecule, prostaglandin E2, which leads to sexually dimorphic patterning of dendritic spine synpases in the POA and resultant male-typical copulatory behavior in adulthood.

Figure 4

There is substantial overlap between neuropsychiatric and neurological disorders that show microglial involvement, sex biases in prevalence or severity, and have developmental origins. Currently, the roles of both sex hormones/sex chromosome complement and microglia in most of these disorders is poorly or incompletely understood.