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

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. Microglial phenotypes: intrinsic properties and physiological roles across the lifespan. Microglia arise mainly from yolk sac primitive macrophages, reside in the brain throughout life, and maintain their numbers through a process of self‐renewal. During development (left panels), growing coverage of the CNS by immature amoeboid macrophages occurs as a result of the rapid proliferation of their population. Maturing microglia increase their number of processes and develop ramified morphologies. They are crucial for the survival of newborn neurons and progenitors, the clearance of apoptotic cells, the formation of dendritic spines, and the pruning of less active synapses. In adulthood (middle panels), ramified microglia are important effectors of plasticity, contributing to ne