Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling
Department of Neurobiology; Brudnick Neuropsychiatric Research Institute; Tapper Lab; Schafer Lab; Graduate School of Biomedical Sciences, Neuroscience Program
Immunopathology | Molecular and Cellular Neuroscience | Nervous System
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.
Cellular neuroscience, Glial biology, Molecular neuroscience, Neural circuits, Neuroscience
DOI of Published Version
Nat Neurosci. 2019 Jul;22(7):1075-1088. doi: 10.1038/s41593-019-0419-y. Epub 2019 Jun 17. Link to article on publisher's site
Gunner G, Johnson KM, Mondo E, Liu L, Tapper AR, Schafer DP. (2019). Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling. Neurobiology Publications and Presentations. https://doi.org/10.1038/s41593-019-0419-y. Retrieved from https://escholarship.umassmed.edu/neurobiology_pp/245