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Review
. 2013 Sep;139(3):313-26.
doi: 10.1016/j.pharmthera.2013.04.013. Epub 2013 Apr 30.

Microglia during development and aging

G Jean Harry  1
Affiliations
Review

Microglia during development and aging

G Jean Harry. Pharmacol Ther. 2013 Sep.

Abstract

Microglia are critical nervous system-specific cells influencing brain development, maintenance of the neural environment, response to injury, and repair. They contribute to neuronal proliferation and differentiation, pruning of dying neurons, synaptic remodeling and clearance of debris and aberrant proteins. Colonization of the brain occurs during gestation with an expansion following birth with localization stimulated by programmed neuronal death, synaptic pruning, and axonal degeneration. Changes in microglia phenotype relate to cellular processes including specific neurotransmitter, pattern recognition, or immune-related receptor activation. Upon activation, microglia cells have the capacity to release a number of substances, e.g., cytokines, chemokines, nitric oxide, and reactive oxygen species, which could be detrimental or beneficial to the surrounding cells. With aging, microglia shift their morphology and may display diminished capacity for normal functions related to migration, clearance, and the ability to shift from a pro-inflammatory to an anti-inflammatory state to regulate injury and repair. This shift in microglia potentially contributes to increased susceptibility and neurodegeneration as a function of age. In the current review, information is provided on the colonization of the brain by microglia, the expression of various pattern recognition receptors to regulate migration and phagocytosis, and the shift in related functions that occur in normal aging.

Keywords: AD; ATP; Aging; Alzheimer's disease; Aβ; BBB; C1q; CD; CNS; CR3; CX3CL1; CX3CR1; Cl(−); Development; GD; IFN; IL; K(+); LPS; MAPK; MHC; Microglia; NO; P2; P2X receptors; PI3K; PND; PRR; Synapse stripping; TGFβ; TLR; TNF; TREM-2; adenosine triphosphate; amyloid beta; blood brain barrier; central nervous system; chloride; cluster of differentiation; complement 1q; complement receptor 3; fractalkine or neurotactin; fractalkine receptor; gestational day; interferon; interleukin; lipopolysaccharide; major histocompatibility complex; mitogen-activated protein kinase; nitric oxide; pattern recognition receptors; phosphoinositide 3-kinase; postnatal day; potassium; purinergic receptors; toll-like receptors; transforming growth factor beta; triggering receptor expressed on myeloid cells-2; tumor necrosis factor.

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Conflict of interest statement

Conflict of Interest Statement

The author declares that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Developmental Stages Leading to Establishment of a Mature Population of Brain Microglia. During gestation (E9 – mice; E11- rat) microglial precursors cross the blood vessel wall and begin to take up residence in the brain parenchyma. Microglia progenitor cells (small round cells) line up along the blood vessels. These cells typically possess little cytoplasm and have small or nonexistent appendages (indicated as process-free round cells with distinct nuclei). At early stages of colonization (approx. E12–15), these cells are identifiable in white matter regions (or along vascular/ ventricular margins) possessing an amoeboid/ phagocytic morphology (larger ruffled round cells [orange]). In the gray matter, the cells are somewhat smaller than in the white matter and begin to show processes. During early postnatal stages (~PND5), these highly proliferative mononuclear cells are observed in both white matter and gray matter regions of the brain with showing both amoeboid and process-bearing phenotypes. During a critical period of postnatal microglia development (PND2- PND14), the number of microglia increases dramatically and has been associated with expression of Runx1. During this time, there is an increased ratio of ramified versus amoeboid microglia, with the cells having noticeably more complex process arbors and cytoplasmic material. By ~PND15 are well distributed throughout the brain and can be seen in close proximity to apoptotic neurons (swollen cells [light brown]), facilitating surveillance of the majority of the parenchyma; they exhibit a significantly reduced proliferative capacity; they begin to exhibit more heterogeneity (both within and across brain regions) in terms of their morphology, orientation, and process field organization; and they begin to express a somewhat modified constellation of cell surface markers. These maturation features continue such that by PND20 the adult population of microglia is fairly well established. In the absence of stimulation, these cells are highly ramified with complex process arbors encompassing the entire brain parenchyma integrated around healthy neurons and they possess little to no evidence of proliferation or from the systemic population (Lawson et al., 1992).
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