Microglia Function in Central Nervous System Development and Plasticity

Abstract

The nervous system comprises a remarkably diverse and complex network of different cell types, which must communicate with one another with speed, reliability, and precision. Thus, the developmental patterning and maintenance of these cell populations and their connections with one another pose a rather formidable task. Emerging data implicate microglia, the resident myeloid-derived cells of the central nervous system (CNS), in the spatial patterning and synaptic wiring throughout the healthy, developing, and adult CNS. Importantly, new tools to specifically manipulate microglia function have revealed that these cellular functions translate, on a systems level, to effects on overall behavior. In this review, we give a historical perspective of work to identify microglia function in the healthy CNS and highlight exciting new work in the field that has identified roles for these cells in CNS development, maintenance, and plasticity.

Figure 1.

Mechanisms involved in microglia-mediated spatial patterning of neurons. (A) The role of microglia in programmed cell death. (a) Microglia can initiate the cell death program through a variety of soluble (e.g., nerve growth factor [NGF], O₂^–, and tumor necrosis factor [TNF]) and membrane-bound (e.g., CD11b and DAP12) factors followed by phagocytosis. (b) Alternatively, apoptosis of neurons or neural precursor cells (NPCs) is induced by unknown mechanisms followed by microglia-mediated phagocytosis of debris. (c) “Phagoptosis” has been described in injury/disease paradigms known to induce inflammation (Brown and Neher 2014) in which microglia actively engulf live cells. Evidence suggests that something similar may be happening in the healthy developing and adult central nervous system (CNS). (B) Microglia can also promote survival of NPCs in the developing CNS. One mechanism identified was insulin-like growth factor (IGF)-1, a soluble factor made and released by microglia, which is believed to bind IGF-1R receptors expressed by a subset of NPCs. It is speculated that those NPCs expressing the receptor survive (a), whereas those that do not express the receptor undergo apoptosis (b).

Figure 2.

The role of microglia in developmental, activity-dependent synaptic remodeling. (A) A model in which microglia selectively engulf a subset of less active, intact synapses. Data suggest that a signal (e.g., fractalkine) recruits microglia to remodeling synapses. Those synapses that are less active (light gray) are molecularly “tagged” with “eat-me” signals (e.g., complement). Microglia, expressing receptors for “eat-me” signals (e.g., CR3), actively select and phagocytose intact synaptic components. (B) A model whereby neurons autonomously begin to prune (retract and/or fragment) before engulfment by microglia. Data suggest that a recruitment signal (e.g., fractalkine) recruits microglia to remodeling synapses. Those synapses that are less active (light gray) begin to autonomously retract and/or fragment. These pruning synapses are subsequently “tagged” with “eat-me” signals (e.g., complement), followed by engulfment by microglia, which express receptors for “eat-me” signals (e.g., CR3).