Microglia detection and phagocytosis of dying neurons is regulated by CX3CR1

ABSTRACT Neuronal cell death is a hallmark of many neurodegenerative diseases. Effective detection and clearance of cell debris generated during cell death events is essential to prevent a degenerative cascade. Brain resident microglia are responsible for performing these functions through complex cell-cell signaling involving both “find-me” and “eat-me” cues. To examine microglial responses to neuronal cell death in vivo, we investigated neuron/microglia CX3CL1/CX3CR1 signaling using intravital optical imaging in mouse cortex and a single-cell ablation technique called 2Phatal. We find that CX3CL1 aggregates as puncta on microglia and that this pattern is maintained when microglia engulf dying neurons. Additionally, disruption of this signaling via Cx3cr1 deletion when both few and many neurons are dying leads to delayed cell corpse clearance, partly due to a delay in microglial engagement with the dying cells. Overall, our work uncovers a precise role for CX3CL1/CX3CR1 signaling in regulating the microglial response to dying neocortical neurons.