Long-Range Ca 2+ Waves Transmit Brain-Damage Signals to Microglia

摘要

Microglia are the resident phagocytes of the brain that are responsible for the clearance of injured neurons, an essential step in subsequent tissue regeneration. How death signals are controlled both in space and time to attract these cells toward the site of injury is a topic of great interest. To this aim, we have used the optically transparent zebrafish larval brain and identified rapidly propagating Ca 2+ waves that determine the range of microglial responses to neuronal cell death. We show that while Ca 2+-mediated microglial responses require ATP, the spreading of intercellular Ca 2+ waves is ATP independent. Finally, we identify glutamate as a potent inducer of Ca 2+-transmitted microglial attraction. Thus, this real-time analysis reveals the existence of a mechanism controlling microglial targeted migration to neuronal injuries that is initiated by glutamate and proceeds across the brain in the form of a Ca 2+ wave. Video Abstract: Using real-time analysis of the developing zebrafish brain, Sieger et al. identify Ca 2+ waves that travel across the brain to guide microglia, the resident phagocytes, to sites of neuronal cell death. Neuronal glutamate/NMDA-receptor signaling generates and propagates these waves, establishing the extracellular ATP guidance cue needed for microglia migration.