Gunner, G., Cheadle, L., Johnson, K. M., Ayata, P., Badimon, A., Mondo, E., Nagy, M. A., Liu, L., Bemiller, S. M., Kim, K. W., Lira, S. A., Lamb, B. T., Tapper, A. R., Ransohoff, R. M., Greenberg, M. E., Schaefer, A., Schafer, D. P.
(July 2019)
Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling.
Nat Neurosci, 22 (7).
pp. 1075-1088.
ISSN 1097-6256 (Print)1097-6256
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.
| Item Type: |
Paper
|
| Subjects: |
bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
organism description > animal
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions
diseases & disorders > inflammation > chemokines
diseases & disorders > inflammation
organism description > animal > mammal
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > microglia
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > microglia
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > microglia
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mRNA
organs, tissues, organelles, cell types and functions
organism description > animal > mammal > rodent
organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction
organs, tissues, organelles, cell types and functions > tissues types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > transcriptomes |
| CSHL Authors: |
|
| Communities: |
CSHL labs > Cheadle lab |
| Depositing User: |
Matthew Dunn
|
| Date: |
July 2019 |
| Date Deposited: |
07 Aug 2020 19:22 |
| Last Modified: |
02 Feb 2024 15:29 |
| PMCID: |
PMC6596419 |
| URI: |
https://repository.cshl.edu/id/eprint/39596 |
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