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Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling

By Georgia Gunner, Lucas Cheadle, Kasey M. Johnson, Pinar Ayata, Ana Badimon, Erica Mondo, Aurel Nagy, Liwang Liu, Shane M. Bemiller, Ki-Wook Kim, Sergio A. Lira, Bruce T. Lamb, Andrew R. Tapper, Richard M. Ransohoff, Michael E. Greenberg, Anne Schaefer, Dorothy Schafer

Posted 15 Feb 2019
bioRxiv DOI: 10.1101/551697 (published DOI: 10.1038/s41593-019-0419-y)

Microglia rapidly respond to changes in neural activity and inflammation to regulate synaptic connectivity. The extracellular signals, particularly neuron-derived molecules, that drive these microglial functions at synapses remains a key open question. Here, whisker lesioning, known to dampen cortical activity, induces microglia-mediated synapse elimination. We show that this synapse elimination is dependent on the microglial fractalkine receptor, CX3CR1, but not complement receptor 3, signaling. Further, mice deficient in the CX3CR1 ligand (CX3CL1) also have profound defects in synapse elimination. Single-cell RNAseq then revealed that Cx3cl1 is cortical neuron-derived and ADAM10, a metalloprotease that cleaves CX3CL1 into a secreted form, is upregulated specifically in layer IV neurons and microglia following whisker lesioning. Finally, inhibition of ADAM10 phenocopies Cx3cr1-/- and Cx3cl1-/- synapse elimination defects. Together, these results identify novel neuron-to-microglia signaling necessary for cortical synaptic remodeling and reveal context-dependent immune mechanisms are utilized to remodel synapses in the mammalian brain.

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