@article{aaada7d9a9d94c0ab43ed71381d2cf35,
title = "Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling",
abstract = "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 remain a key open question. Here we show that whisker lesioning, known to dampen cortical activity, induces microglia-mediated synapse elimination. This synapse elimination is dependent on signaling by CX3CR1, the receptor for microglial fractalkine (also known as CXCL1), but not complement receptor 3. Furthermore, mice deficient in CX3CL1 have profound defects in synapse elimination. Single-cell RNA sequencing revealed that Cx3cl1 is derived from cortical neurons, and ADAM10, a metalloprotease that cleaves CX3CL1 into a secreted form, is upregulated specifically in layer IV neurons and in microglia following whisker lesioning. Finally, inhibition of ADAM10 phenocopies Cx3cr1−/− and Cx3cl1−/− synapse elimination defects. Together, these results identify neuron-to-microglia signaling necessary for cortical synaptic remodeling and reveal that context-dependent immune mechanisms are utilized to remodel synapses in the mammalian brain.",
author = "Georgia Gunner and Lucas Cheadle and Johnson, {Kasey M.} and Pinar Ayata and Ana Badimon and Erica Mondo and Nagy, {M. Aurel} and Liwang Liu and Bemiller, {Shane M.} and Kim, {Ki Wook} and Lira, {Sergio A.} and Lamb, {Bruce T.} and Tapper, {Andrew R.} and Ransohoff, {Richard M.} and Greenberg, {Michael E.} and Anne Schaefer and Schafer, {Dorothy P.}",
note = "Funding Information: The authors thank M. Freeman (OHSU), V. Budnik (UMMS), E. Baehrecke (UMMS), M. Francis (UMMS), P. Greer (UMMS), and R. Bruno (Columbia University) for their critical reading of the manuscript. They also thank the following individuals: M. Ansorage (Columbia University) and S. Nelson (Brandeis University) for providing the SERT-Cre mice; Cahill (UMMS) and A. Lotun (UMMS) for assistance with assessing microglia within the barrel cortex; S. Becker (UMMS) and J. Jung (UMMS) for assistance with tissue preparation and whisker-trimming experiments; H. Learnard (UMMS), A. Song (UMMS), Z. Zhang (Boston Children{\textquoteright}s Hospital), and C. Woolf (Boston Children{\textquoteright}s Hospital) for assistance with experiments to assess ATF3; and D. Bergles (John{\textquoteright}s Hopkins) for advice and discussions related to identification of oligodendrocye precursor cells by Matn4 expression in the single-cell RNA-seq dataset. This work was funded by NIMH-R00MH102351 (D.P.S.), NIMH-R01MH113743 (D.P.S.), NIMH-R21MH115353 (D.P.S. and A.S.), NIH-T32A1095212 (E.M.), the Charles H. Hood Foundation (D.P.S.), the Brain & Behavior Research Foundation (D.P.S.), the Worcester Foundation (D.P.S.), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (D.P.S.). Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = jul,
day = "1",
doi = "10.1038/s41593-019-0419-y",
language = "English",
volume = "22",
pages = "1075--1088",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "7",
}