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C1q is released by microglia, localizes on weak synapses and acts as a tag for microglial synaptic pruning. However, how C1q tags synapses during the pruning period remains to be fully elucidated. Here, we report that C1q is delivered via extracellular vesicles by microglia to pre-synaptic sites that externalize phosphatidylserine. Using approaches to increase or reduce vesicles production in microglia, by C9orf72 knock out or pharmacological inhibition, respectively, we provided mechanistic evidence linking extracellular vesicle release to pre-synaptic remodelling in neuron-microglia cultures. In C9orf72 knockout mice, we confirmed larger production of microglial extracellular vesicles and showed augmented C1q presynaptic deposition associated with enhanced engulfment by microglia in the early postnatal hippocampus. Finally, we provide evidence that microglia physiologically release more vesicles during the period of postnatal circuit refinement. These findings implicate abnormal release of microglial extracellular vesicles in both neurodevelopmental and age-related disorders characterized by dysregulated microglia-mediated synaptic pruning.
D’Arrigo et al. (Mon,) studied this question.