Highlights
•Astrocyte processes reduce contact with synapses before synapse removal by microglia
•Microglia-derived Wnts drive astrocytes to reduce their association with synapses
•Wnt signaling between microglia and astrocytes is critical for synapse remodeling
•Microglia-astrocyte Wnt crosstalk is activated downstream of CX3CL1/CX3CR1 signaling
Summary
Astrocytes and microglia are emerging key regulators of activity-dependent synapse remodeling that engulf and 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 mice to induce activity-dependent synapse removal in the barrel cortex. We show that astrocytes do not engulf synapses in this paradigm. Instead, astrocytes reduce contact with synapses prior to microglia-mediated synapse engulfment. We further show that the reduced astrocyte-synapse contact is dependent on the release 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 instruct astrocyte-synapse interactions, providing a permissive environment for microglia to remove synapses. We further show that this mechanism is critical to remodel synapses in a changing sensory environment and that this signaling is upregulated in several disease contexts.
Graphical abstract
