Roles of microglia in nervous system development, plasticity, and disease

Microglia are a mysterious and historically understudied resident macrophage in the central nervous system (CNS). These cells are important and dynamic regulators of brain cytoarchitecture and inflammation in the context of injury and disease. It is also now becoming increasingly clear that microglia are a fairly heterogeneous, sexually dimorphic population of cells, performing important functions throughout the healthy vertebrate brain. Microglia are crucial for CNS development and for regulating homeostasis and plasticity in adulthood. In vivo imaging studies have revealed that the fine processes of microglia in the healthy brain are highly motile, dynamically surveying their environment, associating with synaptic elements, and surveying for injury. Microglial processes regularly contact surrounding neurons to monitor and alter synaptic firing rates. During development, they assist in sculpting synaptic circuits by stimulating the growth of new synapses and phagocytosing weak or unnecessary ones. They also appear to regulate the development and/or maintenance of other cell types including astrocytes, oligodendrocytes, and the vasculature. In this special issue of Developmental Neurobiology, we’ve brought together articles by leaders in the field discussing what we currently know about microglia in health, trying to find answers to central questions. How and why do microglia modulate neuronal activity? What are their roles in the developing brain? Do the differences in microglial cells between females and males contribute to sexual dimorphism? Are microglia heterogeneous in the brain, and does this heterogeneity translate to diverse functions depending on the brain region? These questions demand expertise in a variety of fields such as immunology, neuroscience, development, genetics, behavioral and cell science, and answers must be sought by utilizing diverse sets of tools and techniques. The study of microglia is truly an integrative pursuit, and we present here reviews and original research that highlight how the field has come together to answer these questions. York and MacVicar (2018) describe how microglia sense and modulate neuronal activity in the healthy brain. Microglia have long processes that they use to monitor the surrounding area, often making direct contact with neurons. They can monitor neuronal activity by sensing neuronal release of ATP, glutamate, serotonin, c-aminobutyric acid (GABA), acetylcholine, and fractalkine. Interestingly, microglia can increase or decrease neuronal firing and help mediate synaptic remodeling, which is necessary in experience-dependent learning. Indeed, deficits in motor learning and memory result from ablating these microglial activities. In a research study by Stowell et al. (2018), mouse cerebellar microglia were found to interact with Purkinje neurons in vivo, contacting their dendritic arbors and somas. These cerebellar microglia are distinct from mouse cortical microglia in that they are sparsely distributed and less ramified, resulting in decreased parenchymal surveillance by microglial processes in the cerebellum. However, cerebellar microglia have a novel form of somal motility: instead of only moving their processes, they can move their entire cell body. Differences between microglia in various regions and under various conditions is actually quite common. Indeed, microglia have region-specific phenotypes and will change their phenotype under conditions of disease and injury. They also perform different functions during development, such as engulfing synapses, which means their phenotypes can change across time. Lopez-Atalaya et al. (2018) describe the factors regulating the identity and plasticity of brain macrophages, including microglia. Signals from the local microenvironment play a large role in determining and maintaining microglial cell identity, while transcriptional programs play a large role in their initial differentiation. Interestingly, microglia are not derived from the usual immune precursor cells and are present in the brain before even the vasculature has formed. 2018 Wiley Periodicals, Inc. Published online 6 April 2018 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/dneu.22594