Abstract
The relationship between the central nervous system (CNS) and microglia is lifelong. Microglia originate in the embryonic yolk sac during development and populate the CNS before the blood-brain barrier forms. In the CNS, they constitute a self-renewing population. Although they represent up to 10% of all brain cells, we are only beginning to understand how much brain homeostasis relies on their physiological functions. Often compared to a double-edged sword, microglia hold the potential to exert neuroprotective roles that can also exacerbate neurodegeneration once compromised. Microglia can promote synaptic growth in addition to eliminating synapses that are less active. Synaptic loss, which is considered one of the best pathological correlates of cognitive decline, is a distinctive feature of major depressive disorder (MDD) and cognitive aging. Long-term psychological stress accelerates cellular aging and predisposes to various diseases, including MDD, and cognitive decline. Among the underlying mechanisms, stress-induced neuroinflammation alters microglial interactions with the surrounding parenchymal cells and exacerbates oxidative burden and cellular damage, hence inducing changes in microglia and neurons typical of cognitive aging. Focusing on microglial interactions with neurons and their synapses, this review discusses the disrupted communication between these cells, notably involving fractalkine signaling and the triggering receptor expressed on myeloid cells (TREM). Overall, chronic stress emerges as a key player in cellular aging by altering the microglial sensome, notably via fractalkine signaling deficiency. To study cellular aging, novel positron emission tomography radiotracers for TREM and the purinergic family of receptors show interest for human study.
Highlights
Since their discovery, microglia have been described as the resident macrophages of the central nervous system (CNS)
Microglial distribution, which was discovered to be greater in the white matter, varied from 0.3 to 16.9% of all brain cells depending on the region (Mittelbronn et al, 2001)
We describe recent discoveries on the bidirectional communication between microglia, neurons, and their synapses, as well as discuss how their interactions are altered upon psychological stress and in major depressive disorder (MDD), leading to accelerated brain and cognitive aging
Summary
Microglia have been described as the resident macrophages of the central nervous system (CNS) They migrate from the yolk sac to the brain around embryonic day 9.5 in mice (Ginhoux et al, 2010) and can be observed for the first time in the developing human brain around the 4.5–5th week of gestation (Andjelkovic et al, 1998; Monier et al, 2006; Verney et al, 2010). Following their migration and colonization, microglia remain distributed unevenly between the gray and white matters and across individual brain regions (Lawson et al, 1990; Mittelbronn et al, 2001). Microglial numbers are maintained through local self-renewal in physiological conditions, a phenomenon conserved across species (Lawson et al, 1992; Askew et al, 2017; Füger et al, 2017; Réu et al, 2017; Tay et al, 2017)
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