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Towards a dynamic quantitative understanding of neuronal microglial interactions

Final Report Summary - FPMICROGLIA (Towards a dynamic quantitative understanding of neuronal microglial interactions.)

One central topic in cell and developmental biology is how phagocytes engulf dying cells. Unfortunately, the spatial and temporal dynamics of this process is poorly understood due to an inability to image these events in vivo and to visualize signals in intact tissues. Here, we discovered glutamate-dependent rapid Ca2+ waves that travel across the brain to guide microglia, the brain phagocytes, towards neuronal injuries. Preventing their formation by extracellular calcium chelation is sufficient to suppress microglial targeting to damage sites, whereas ectopic induction of Ca2+ signals by photo-uncaging mimics the attraction of microglia to neuronal injury. Moreover, by taking a quantitative live imaging approach we have investigated neuronal–microglial interactions at single-cell resolution. This led to the identification of TIM-4 and BAI1, two phagocytic receptors that work together to allow microglia to remove dying neurons. In particular, by combining live-imaging and reverse genetics we have found that BAI1 is needed to form and to transport phagosomes containing dying neurons, while TIM-4 stabilizes these structures.