Real-time mechanisms of exacerbated synaptic remodeling by microglia in acute models of systemic inflammation and tauopathy

Remodeling of synapses by microglia is essential for synaptic plasticity in the brain. However, during neuro-inflammation and neurodegenerative diseases, microglia can induce excessive synaptic loss, although the precise underlying mechanisms are unknown. To directly observe microglia-synapse interactions under inflammatory conditions, we performed in vivo two-photon time-lapse imaging of microglia-synapse interactions after bacterial lipopolysaccharide administration to model systemic inflammation, or after inoculation of Alzheimer's disease (AD) brain extracts to model disease-associated neuroinflammatory microglial response. Both treatments pro-longed microglia-neuron contacts, decreased basal surveillance of synapses and promoted synaptic remodeling in response to synaptic stress induced by focal single-synapse photodamage. Spine elimination correlated with the expression of microglial complement system/phagocytic proteins and the occurrence of synaptic filopodia. Microglia were observed contacting spines, then stretching and phagocytosing spine head filopodia. Thus, in response to inflammatory stimuli microglia exacerbated spine remodeling through prolonged microglial contact and elimination of spines 'tagged' by synaptic filopodia.

Automated summary

Remodeling of synapses by microglia is critical for synaptic plasticity in the brain. In neuro-inflammation and neurodegenerative diseases, microglia can cause excessive synaptic loss, and this study investigated the underlying mechanisms by observing microglia-synapse interactions under inflammatory conditions. The findings showed that inflammatory stimuli prolonged microglia-neuron contacts, decreased surveillance of synapses, and promoted synaptic remodeling through the elimination of spines tagged by synaptic filopodia.