Microglia across the lifespan: from origin to function in brain development, plasticity and cognition

Abstract

Microglia are the only immune cells that permanently reside in the central nervous system (CNS) alongside neurons and other types of glial cells. The past decade has witnessed a revolution in our understanding of their roles during normal physiological conditions. Cutting-edge techniques revealed that these resident immune cells are critical for proper brain development, actively maintain health in the mature brain, and rapidly adapt their function to physiological or pathophysiological needs. In this review, we highlight recent studies on microglial origin (from the embryonic yolk sac) and the factors regulating their differentiation and homeostasis upon brain invasion. Elegant experiments tracking microglia in the CNS allowed studies of their unique roles compared with other types of resident macrophages. Here we review the emerging roles of microglia in brain development, plasticity and cognition, and discuss the implications of the depletion or dysfunction of microglia for our understanding of disease pathogenesis. Immune activation, inflammation and various other conditions resulting in undesirable microglial activity at different stages of life could severely impair learning, memory and other essential cognitive functions. The diversity of microglial phenotypes across the lifespan, between compartments of the CNS, and sexes, as well as their crosstalk with the body and external environment, is also emphasised. Understanding what defines particular microglial phenotypes is of major importance for future development of innovative therapies controlling their effector functions, with consequences for cognition across chronic stress, ageing, neuropsychiatric and neurological diseases.

Figure 1. Signalling pathways regulating microglial proliferation, maturation and homeostasis in healthy and diseased conditions

The proper development, differentiation, proliferation and function of both microglia and neurons require a continuous and lifelong crosstalk between the two cell types via complementary ligands and receptors and secreted trophic factors (e.g. cytokines). As microglia (blue) and neurons (brown) mature, they downregulate certain signalling pathways (e.g. Cxcl12‐Cxcr4) and upregulate others (e.g. IL‐34‐Csf‐1R). Dysregulation of either ligands or receptors occurs in a number of disease processes (dysfunctional microglia, purple). Maturation of yolk sac derived microglia within the CNS is dependent on proper signalling via purinergic receptors and cell surface protein Csf‐1R. Similarly, mature microglia require functional Csf‐1R signalling for their maintenance. Microglial ‘signature’ factors recently identified include TGFβ (transforming growth factor β, which appears critical for mediating microglial survival and phenotypic differentiation in the healthy mature brain) and Tmem119 (transmembrane protein 119, a cell surface protein of unknown function). The expression of microglial markers (including IBA1, CD45, MHC class II, and others) is often changed during the course of ageing and disease, coincident with changes in microglial function. R, receptors.