Microglia-dependent remodeling of neuronal circuits

Abstract

Microglia are tissue-resident macrophages responsible for the surveillance, neuronal support, and immune defense of the brain parenchyma. Recently, the role played by microglia in the formation and function of neuronal circuits has garnered substantial attention. During development, microglia have been shown to engulf neuronal precursors and participate in pruning mechanisms while, in the mature brain, they influence synaptic signaling, provide trophic support and shape synaptic plasticity. Recently, studies have unveiled different microglial characteristics associated with specific brain regions. This emerging view suggests that the maturation and function of distinct neuronal circuits may be potentially associated with the molecular identity microglia adopts across the brain. Here, we review and summarize the known role of these cells in the thalamus, hippocampus, cortex, and cerebellum. We focus on in vivo studies to highlight the characteristics of microglia that may be important in the remodeling of these neuronal circuits and in relation to neurodevelopmental and neuropsychiatric disorders.

Keywords: brain wiring; cerebellum; cortex; hippocampus; microglia; neurodevelopment; thalamus.

FIGURE 1

Microglia ontogeny and development. Microglia derive from primitive CD45⁻ c‐kit⁺ hematopoietic progenitors of the extra‐embryonic yolk sac (YS), that mature to CD45⁺ c‐kit⁻ progenitors between E9.5 and 14. During this time, microglia begin the colonization of the neural tube and start to express CX3CR1, the fractalkine receptor, and CSFR1. In the rudimentary brain, microglia develop at different paces, with microglia from the cortex, for example, developing faster than those of the cerebellum, becoming more ramified and less amoeboid at an earlier age. CSFR1 signaling, required for proper microglia development, is mediated by M‐CSF in the cerebellum, while in the rest of the brain this is promoted by IL‐34.

FIGURE 2

Microglia matures alongside neuronal circuits. As brain circuits develop, microglia colonize and mature alongside in a bidirectionally regulated process. During this time, these cells participate in several of developmental steps, from neurogenesis to synaptogenesis and circuit refinement through synaptic pruning, being essential for the proper establishment of these circuits.

FIGURE 3

The many roles of microglia throughout development. Microglia participate in key steps of brain development and are essential for the proper shaping of neuronal circuits. These cells play an important role in ensuring proper neuronal migration and axonal connectivity, trimming excess neurons, and clearing apoptotic cells and debris. Microglia also extensively engage in the regulation of synapses, performing either synaptic pruning or promoting synaptogenesis, providing support, and modulating synaptic plasticity to ensure proper neuronal connectivity.