Neuroinflammation triggers microglial phagocytosis of synapses via induction of synaptic filopodia

Abstract Activated microglia play a significant role in synaptic elimination during neuroinflammation, however, the events prior to the uptake of synaptic material by these cells remain elusive. Here, we performed in vivo two-photon imaging of microglia-synapse interactions in the context of systemic inflammation and Alzheimer´s disease. Both treatments induced microglial activation and decreased the basal surveillance of synapses by microglia. Focal synaptic stress was necessary to promote long-lasting microglia-neuron contacts and exacerbate spine elimination. The rate of spine elimination strongly correlated with the frequency of synaptic filopodia generation and microglial expression of phagocytic proteins. We show that activated microglia largely eliminate spines through phagocytosis rather than promoting their rapid retraction into dendrites. Moreover, we found that activated microglia induce the physical stretching of spines and their phagocytosis via the induction of spine head filopodia. Our real-time observations highlight key factors and decision points governing synaptic elimination by microglia during neuroinflammation.