RT Journal Article
SR Electronic
T1 Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 551697
DO 10.1101/551697
A1 Georgia Gunner
A1 Lucas Cheadle
A1 Kasey M. Johnson
A1 Pinar Ayata
A1 Ana Badimon
A1 Erica Mondo
A1 Aurel Nagy
A1 Liwang Liu
A1 Shane M. Bemiller
A1 Ki-Wook Kim
A1 Sergio A. Lira
A1 Bruce T. Lamb
A1 Andrew R. Tapper
A1 Richard M. Ransohoff
A1 Michael E. Greenberg
A1 Anne Schaefer
A1 Dorothy P. Schafer
YR 2019
UL http://biorxiv.org/content/early/2019/02/15/551697.abstract
AB 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.