Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling

• Published in: Nature neuroscience Vol. 22; no. 7; pp. 1075 - 1088
• Main Authors: Gunner, Georgia, Cheadle, Lucas, Johnson, Kasey M., Ayata, Pinar, Badimon, Ana, Mondo, Erica, Nagy, M. Aurel, Liu, Liwang, Bemiller, Shane M., Kim, Ki-Wook, Lira, Sergio A., Lamb, Bruce T., Tapper, Andrew R., Ransohoff, Richard M., Greenberg, Michael E., Schaefer, Anne, Schafer, Dorothy P.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2019; Nature Publishing Group
• Subjects: 14; 14/19; 38; 38/91; 631/378; 631/378/2596; 631/378/340; 631/378/3920; 631/378/87; 64; 64/110; 64/60; 96; ADAM10 Protein - antagonists & inhibitors; ADAM10 Protein - genetics; ADAM10 Protein - physiology; Alzheimer's disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - physiology; Analysis; Animal Genetics and Genomics; Animals; Apoptosis; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Brain research; Cell Count; Chemokine CX3CL1 - physiology; Complement receptor 3; Control; CX3C Chemokine Receptor 1 - deficiency; CX3C Chemokine Receptor 1 - genetics; CX3C Chemokine Receptor 1 - physiology; CX3CR1 protein; Defects; Female; Fractalkine; Gene Expression Regulation; Gene sequencing; Ligands; Male; Medicine; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - physiology; Metalloproteinase; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfluidic Analytical Techniques; Microglia; Microglia - physiology; Neural networks; Neural transmission; Neurobiology; Neurons; Neurosciences; Physiological aspects; Ribonucleic acid; RNA; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Sensorimotor Cortex - metabolism; Sensorimotor Cortex - pathology; Sensorimotor Cortex - physiopathology; Signal Transduction - physiology; Signaling; Single-Cell Analysis; Synapse elimination; Synapses; Touch - physiology; Transcriptome; Vibrissae; Vibrissae - injuries; Vibrissae - physiology; United States
• ISSN: 1097-6256; 1546-1726; 1546-1726
• 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 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. Microglia are resident immune cells of the CNS. Here the authors show that neurons communicate to microglia via activity-dependent fractalkine and ADAM10 signaling to induce removal of synapses in the brain after sensory loss.