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Microglia and astrocytes have been implicated in remodeling synapses, but whether and how these cells coordinate to remodel synapses remain open questions. Here, we have identified key mechanistic underpinnings by which microglia instruct astrocytes to modify their synaptic coverage to enable synapse removal. We are further identifying how the degree of astrocyte synapse ensheathment can dictate windows of plasticity to enable microglia-mediated synapse remodeling in health and disease.