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0 reviewsSUMMARYAstrocytes and microglia are emerging key regulators of activity-dependent synapse remodeling that engulfand remove synapses in response to changes in neural activity. Yet, the degree to which these cells communicate to coordinate this process remains an open question. Here, we use whisker removal in postnatal miceto induce activity-dependent synapse removal in the barrel cortex. We show that astrocytes do not engulfsynapses in this paradigm. Instead, astrocytes reduce contact with synapses prior to microglia-mediatedsynapse engulfment. We further show that the reduced astrocyte-synapse contact is dependent on therelease of Wnts from microglia downstream of neuron-to-microglia fractalkine ligand-receptor (CX3CL1-CX3CR1) signaling. These results demonstrate an activity-dependent mechanism by which microglia instructastrocyte-synapse interactions, providing a permissive environment for microglia to remove synapses. Wefurther show that this mechanism is critical to remodel synapses in a changing sensory environment andthat this signaling is upregulated in several disease contexts.