Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling

Georgia Gunner, Lucas Cheadle, Kasey M. Johnson, Pinar Ayata, Ana Badimon, Erica Mondo, M. Aurel Nagy, Liwang Liu, Shane M. Bemiller, Ki Wook Kim, Sergio A. Lira, Bruce Lamb, Andrew R. Tapper, Richard M. Ransohoff, Michael E. Greenberg, Anne Schaefer, Dorothy P. Schafer

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1075-1088
Number of pages14
JournalNature Neuroscience
Volume22
Issue number7
DOIs
StatePublished - Jul 1 2019
Externally publishedYes

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Chemokine CX3CL1
Synapses
Microglia
Neurons
Vibrissae
Macrophage-1 Antigen
RNA Sequence Analysis
Metalloproteases
Inflammation
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Gunner, G., Cheadle, L., Johnson, K. M., Ayata, P., Badimon, A., Mondo, E., ... Schafer, D. P. (2019). Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling. Nature Neuroscience, 22(7), 1075-1088. https://doi.org/10.1038/s41593-019-0419-y

Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling. / 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; Tapper, Andrew R.; Ransohoff, Richard M.; Greenberg, Michael E.; Schaefer, Anne; Schafer, Dorothy P.

In: Nature Neuroscience, Vol. 22, No. 7, 01.07.2019, p. 1075-1088.

Research output: Contribution to journalArticle

Gunner, G, Cheadle, L, Johnson, KM, Ayata, P, Badimon, A, Mondo, E, Nagy, MA, Liu, L, Bemiller, SM, Kim, KW, Lira, SA, Lamb, B, Tapper, AR, Ransohoff, RM, Greenberg, ME, Schaefer, A & Schafer, DP 2019, 'Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling', Nature Neuroscience, vol. 22, no. 7, pp. 1075-1088. https://doi.org/10.1038/s41593-019-0419-y
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 ; Tapper, Andrew R. ; Ransohoff, Richard M. ; Greenberg, Michael E. ; Schaefer, Anne ; Schafer, Dorothy P. / Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling. In: Nature Neuroscience. 2019 ; Vol. 22, No. 7. pp. 1075-1088.
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