Fine-tuning the central nervous system: microglial modelling of cells and synapses

Abstract

Microglia constitute as much as 10-15% of all cells in the mammalian central nervous system (CNS) and are the only glial cells that do not arise from the neuroectoderm. As the principal CNS immune cells, microglial cells represent the first line of defence in response to exogenous threats. Past studies have largely been dedicated to defining the complex immune functions of microglial cells. However, our understanding of the roles of microglia has expanded radically over the past years. It is now clear that microglia are critically involved in shaping neural circuits in both the developing and adult CNS, and in modulating synaptic transmission in the adult brain. Intriguingly, microglial cells appear to use the same sets of tools, including cytokine and chemokine release as well as phagocytosis, whether modulating neural function or mediating the brain's innate immune responses. This review will discuss recent developments that have broadened our views of neuro-glial signalling to include the contribution of microglial cells.

Keywords: cerebral cortex; microglia; neuroblasts; neurogenesis; neurons; synapse.

Figure 1.

Microglial origin and establishment in the CNS. (a) Microglia cells undergo pronounced morphological changes once inside the CNS, from amoeboid immature cells to the typical ramified microglia observed throughout the brain parenchyma. (b) Remarkably, these changes in microglia morphology occur inside a tissue with an ontogenetically distinct origin, and microglia cells are exposed to several signalling molecules, including ECM proteins, cyto- and chemokines and growth factors of neural origin. Microglia derive from a restricted subpopulation of yolk sac erythromyeloid progenitors [17,18] that express the transcription factors SPI1/Pu.1⁺ and Irf8⁺ [19] and enter the CNS during embryonic (E) stages E8.5–E9.5. At neonatal stages (P0–P3), amoeboid microglia populate the neural parenchyma through the meninges and ventricular system and use vessels and RG cell processes as migratory scaffold. Once established, microglia undergo proliferation and spread in the cerebral cortex (Ctx) parenchyma (P5–P15), acquiring their mature morphology, which is observed throughout the cortical layers. (c) Laser scanning micrographic of CX3CR1-EGFP⁺ cells (green) shows CNS invasion by amoeboid microglia through the LV. (d) Microglial cell labelled by Isolectin B₄ (green) displaying a migratory morphology attaches to RG processes (GFAP⁺, magenta) to populate the cortical parenchyma. (e) At neonatal stages, microglial cells (CX3CR1-EGFP⁺ cells, green) markedly increase in number in the WM. (f) In the adult brain, microglia (CX3CR1-EGFP⁺ cells, green) are widely distributed in the CNS parenchyma and exhibit a ramified morphology. BBB, blood–brain barrier; ECM, extracellular matrix; SVZ, subventricular zone. Scale bars: (c, d and inset in f) 10 µm, (e) 20 µm and (f) 500 µm.

Figure 2.

Microglia classical and non-classical functions. (a) Toxic stimuli trigger microglial activation, which reacquire their migratory capacity and reassume the amoeboid morphology. Activated microglia release proinflammatory cytokines and superoxides that mediate phagocytosis of damaged cells. Under severe conditions, microglia-released proinflammatory cytokines recruit circulating monocytes, which can enter the CNS through disrupted blood–brain barrier. (b) Alternative functions have been proposed for microglial cells and microglia-released molecules in the physiological conditions. Microglia act as pivotal synapse regulatory elements through the release of neurotransmitters, such as glycine [20] and ATP [21], chemokine signalling (FKN/CX3CR1 [22]) and cytokines (TNF-α [23,24]). In vivo, microglial cells have been shown to be an important trophic source for neurons (IGF-1/IGF-1R [10]) and phagocyte newborn neurons in the cerebellum [11], and act on synaptic pruning via FKN/CX3CR1 signalling pathway [13] and through C3/CR3 cascade [14]. In the adult CNS, although the molecules mediating non-classical microglia functions remain elusive, microglia establish critical synapse contact [25] and phagocytose a great part of newly generated neuronal precursors in the hippocampus [15].