Microglia: Driving critical periods and sexual differentiation of the brain - PubMed (original) (raw)

Review

. 2018 Jun;78(6):580-592.

doi: 10.1002/dneu.22569. Epub 2018 Jan 3.

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Review

Microglia: Driving critical periods and sexual differentiation of the brain

Jonathan W VanRyzin et al. Dev Neurobiol. 2018 Jun.

Abstract

The proverbial role of microglia during brain development is shifting from passive members of the brain's immune system to active participants that are able to dictate enduring outcomes. Despite these advances, little attention has been paid to one of the most critical components of early brain development-sexual differentiation. Mounting evidence suggests that the normal developmental functions microglia perform-cell number regulation and synaptic connectivity-may be involved in the sex-specific patterning of the brain during these early sensitive periods, and may have lasting sex-dependent and sex-independent effects on behavior. In this review, we outline the known functions of microglia during developmental sensitive periods, and highlight the role they play in the establishment of sex differences in brain and behavior. We also propose a framework for how researchers can incorporate microglia in their study of sex differences and vice versa. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 580-592, 2018.

Keywords: behavior; brain development; critical (sensitive) period; microglia; neuroimmunology; sex differences; sexual differentiation.

© 2017 Wiley Periodicals, Inc.

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Conflict of interest statement

Conflict of interest statement: No conflicts of interest

Figures

Figure 1

Figure 1. Sexual differentiation of the brain and behavior

A male fetus carries a gene on the SRY gene on the Y chromosome and this gene codes for a protein called Testis Determining Factor which differentiates the biopotential gonad into testes. The testes synthesize testosterone which is converted to estradiol in some areas of the brain by the enzyme aromatase. In the preoptic area, estradiol exposure in males and females ultimately triggers microglia to assume an ameboid morphology and begin producing prostaglandin (PGE2) which acts on neurons to organize a 2-fold higher synaptic density pattern that is necessary for male copulatory behavior later in life. Post-puberty and in adulthood the organized (masculinized) POA is activated by circulating gonadal steroids to enable male sexual behavior.

Figure 2

Figure 2. Microglial morphology is variable during the critical period for sexual differentiation

Microglia originate in the yolk sac and migrate into the brain during embryogenesis. These cells are capable of morphological plasticity at all stages of life during and after insult. Under normal conditions, however, microglia exhibit an especially dynamic array of morphologies during the critical period for sexual differentiation of the brain. These morphologies range from (left to right above) ameboid, stout, transitioning, ramified and phagocytic. The critical period for sexual differentiation of the brain is defined by the surge in testicular hormones and their metabolites in males perinatally. Sex differences in microglial morphologies during the critical period have been identified in many regions of the brain, however, these differences often disappear, or are even reversed, at the close of the critical period for sexual differentiation.

Figure 3

Figure 3. Microglia modulate sexually differentiated endpoints

During the critical period for sexual differentiation microglia help to modulate fundamental processes from cell genesis to migration, differentiation, synaptogenesis and cell death, all of which differ in males and females in at least one brain region. Abbreviations: CR3, complement receptor 3; DAP12, DNAX-activation protein 12; Insulin-like growth factor 1; IL, interleukin; LIF, leukemia inhibitory factor; NF-kB, nuclear factor-kappaB; NGF, nerve growth factor; Tim-4, Tcell, immunoglobulin, mucin 4.

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