Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling

Abstract

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 their contact with synapses prior to microglia-mediated synapse engulfment. We further show that reduced astrocyte-contact with synapses is dependent on microglial CX3CL1-CX3CR1 signaling and release of Wnts from microglia following whisker removal. These results demonstrate an activity-dependent mechanism by which microglia instruct astrocyte-synapse interactions, which then provides 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 this signaling is upregulated in several disease contexts.

CRISPRi-based screen of Autism Spectrum Disorder risk genes in microglia uncovers roles ofADNPin microglia endocytosis and uptake of synaptic material

“…We also provide preliminary evidence for WNT signaling playing a role in the uptake of synaptic material. Recent work has provided evidence for WNT signaling by microglia coordinating retraction of astrocytic processes from synapses to promote synaptic remodeling in a whisker deprivation paradigm 46 . Our data offers a complimentary yet new insight into the role of WNT signaling between neurons and microglia.…”