In vivo imaging of the phagocytic dynamics underlying efficient clearance of adult-born hippocampal granule cells by ramified microglia.

Abstract

The phagocytosis of dead cells by microglia is essential in brain development and homeostasis. However, the mechanism underlying the efficient removal of cell corpses by ramified microglia remains poorly understood. Here, we investigated the phagocytosis of dead cells by ramified microglia in the hippocampal dentate gyrus, where adult neurogenesis and homeostatic cell clearance occur. Two-color imaging of microglia and apoptotic newborn neurons revealed two important characteristics. Firstly, frequent environmental surveillance and rapid engulfment reduced the time required for dead cell clearance. The motile microglial processes frequently contacted and enwrapped apoptotic neurons at the protrusion tips and completely digested them within 3-6 h of the initial contact. Secondly, while a single microglial process engaged in phagocytosis, the remaining processes continued environmental surveillance and initiated the removal of other dead cells. The simultaneous removal of multiple dead cells increases the clearance capacity of a single microglial cell. These two characteristics of ramified microglia contributed to their phagocytic speed and capacity, respectively. Consistently, the cell clearance rate was estimated to be 8-20 dead cells/microglia/day, supporting the efficiency of removing apoptotic newborn neurons. We concluded that ramified microglia specialize in utilizing individual motile processes to detect stochastic cell death events and execute parallel phagocytoses.