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Negative feedback control of neuronal activity by microglia

Badimon, Ana and Strasburger, Hayley J. and Ayata, Pinar and Chen, Xinhong and Nair, Aditya and Ikegami, Ako and Hwang, Philip and Chan, Andrew T. and Graves, Steven M. and Uweru, Jospeh O. and Ledderose, Carola and Gunes Kutlu, Munir and Wheeler, Michael A. and Kahan, Anat and Ishikawa, Masago and Wang, Ying-Chih and Loh, Yong-Hwee E. and Jiang, Jean X. and Sumeier, D. James and Robson, Simon C. and Junger, Wolfgang G. and Sebra, Robert and Calipari, Erin S. and Kenny, Paul J. and Eyo, Ukpong B. and Colonna, Marco and Qunitana, Francisco J. and Wake, Hiroaki and Gradinaru, Viviana and Schaefer, Anne (2020) Negative feedback control of neuronal activity by microglia. Nature, 586 (7829). pp. 417-423. ISSN 0028-0836. doi:10.1038/s41586-020-2777-8.

[img] Image (JPEG) (Extended Data Fig. 1: DREADD-based mouse models to study microglia responses to neuronal activation and inhibition reveals distinct microglia responses) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 2: Microglia deficient mice show normal baseline behaviours but exaggerated responses to neurostimulants) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 3: Generation and characterization of Il34-deficient and Csf1-deficient mice) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 4: Generation of mice with striatum-specific microglia depletion) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 5: Striatum-specific microglia reduction has no overall effects on striatal cellular composition, D1/D2 neuronal morphology, D1/D2 MSN characteristic electrophysiological and molecular phenotypes, and glial phenotypes) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 6: Microglia regulate striatal neuron synchrony and responses to D1 agonist treatment in an ADO/A1R dependent fashion) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 7: Microglial expression of Entpd1/CD39 and Nt5e/CD73 in vitro and in vivo) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 8: Microglia suppress neuronal activation via an ATP/AMP/ADO/A1R- dependent feedback mechanism) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 9: Microglia can suppress glutamate-induced cortical neuron activation in a CD39/ADO/A1R-dependent fashion in vitro) - Supplemental Material
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[img] Image (JPEG) (Extended Data Fig. 10: Reactive microglia in different neuroinflammatory and neurodegenerative conditions show a reduction in Entpd1 and P2ry12 expression that is associated with an A1R-dependent increase in D1 neuron responses) - Supplemental Material
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Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival1. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A1R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.

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Chen, Xinhong0000-0003-0408-0813
Gradinaru, Viviana0000-0001-5868-348X
Additional Information:© 2020 Springer Nature Limited. Received 26 November 2019. Accepted 28 August 2020. Published 30 September 2020. We thank P. Greengard and A. Nairn for sharing the DARPP32 antibodies; J. J. Badimon for the Ticagrelor and Clopidogrel; R. Greene for the Adora1^(fl/fl) mice; M. Merad and F. Desland for the Csf1^(fl/fl); Nestin^(Cre) mice, the MSSM FACS facility and J. Ochando, C. Bare, and G. Viavattene for assistance with flow cytometry analysis; A. Lopez and A. Watters for assistance with microdialysis experiments; G. Milne and the Vanderbilt University Neurochemistry Core for LC–MS analysis; D. Wagenaar and CalTech Neurotechnology Laboratory for help with construction of the two-photon system; and all Schaefer laboratory members and A. Tarakhovsky for discussions and critical comments on the manuscript. This work was supported by the National Institutes of Health (NIH) Director New Innovator Award DP2 MH100012-01 (A.S.), NIH grants R01NS091574 (A.S.), R01MH118329 (A.S.), DA047233 (A.S.), R01NS106721 (A.S.) and U01AG058635 (A.S.), a Robin Chemers Neustein Award (P.A.), NIH grant RO1AG045040 (J.X.J.), Welch Foundation Grant AQ-1507 (J.X.J.), NARSAD Young Investigator Award no. 25065 (P.A.), NIH grants T32AG049688 (A.B.), T32AI078892 (A.T.C.), 1K99NS114111 (M.A.W.), T32CA207201 (M.A.W.), R01NS102807 (F.J.Q.), R01AI126880 (F.J.Q.), and R01ES025530 (F.J.Q.), a TCCI Chen Graduate Fellowship (X.C.), an A*STAR National Science Scholarship (A.N.), the CZI Neurodegeneration Challenge Network (V.G.), NIH BRAIN grant RF1MH117069 (V.G.), NIH grants HL107152 (S.C.R.), HL094400 (S.C.R.), AI066331 (S.C.R.), GM-136429 (W.G.J.), GM-51477 (W.G.J.), GM-116162 (W.G.J.), HD-098363 (W.G.J.), DA042111 (E.S.C.), DA048931 (E.S.C.), funds from a VUMC Faculty Research Scholar Award (M.G.K.), the Brain and Behavior Research Foundation (M.G.K. and E.S.C), the Whitehall Foundation (E.S.C.), and the Edward Mallinckrodt Jr. Foundation (E.S.C.). The Vanderbilt University Neurochemistry Core is supported by the Vanderbilt Brain Institute and the Vanderbilt Kennedy Center (EKS NICHD of NIH Award U54HD083211). Data availability. The gene expression data related to this study are available at the NCBI Gene Expression Omnibus (GEO) under accession number GSE149897. Source data are provided with this paper. Code availability. The code used for analysis of calcium transience in neurons to analyse event rates, magnitude, spatial correlation and synchrony can be found at Author Contributions. A.S. and A.B. conceived and designed the study. A.B. did molecular, behavioural, FACS and imaging experiments. H.J.S. did primary neuronal culture, microglia isolation, microglia culture, FACS and Axion microelectrode array experiments. P.A. did in vivo TRAP experiments. A.B., X.C., A.N., V.G. and A.S. designed two-photon imaging experiments, which were performed by X.C. and A.N. A.K. built the customized two-photon system. A.B., A.I., H.W. and A.S. designed the two-photon imaging of microglial protrusions, which was performed by A.I. A.T.C. and R.S. performed single-nucleus 10X sequencing. Y.-C.W. analysed single-nucleus 10X sequencing data. Y.-H.E.L. analysed bulk RNA-seq data from TRAP experiments. A.S., D.J.S. and S.M.G. designed experiments to measure neuronal excitability that were conducted by S.M.G. A.B., M.I., P.J.K. and A.S. designed experiments to measure sEPSCs that were conducted by M.I. A.S. and A.B. designed and P.H. performed molecular and imaging experiments. C.L. and W.G.J. conducted the HPLC analysis. M.G.K. and E.S.C. conducted the microdialysis experiments. A.B., J.O.U. and U.B.E. conducted seizure susceptibility experiments on P2ry12−/− mice. S.C.R. generated Cd39fl/fl mice. J.X.J. generated Csf1fl/fl mice. M.C. generated Il34fl/fl mice. M.A.W. and F.J.Q. generated Cd39fl/flCx3cr1CreErt2/+(Jung) mice. A.B., M.A.W., F.J.Q. and A.S. designed behavioural experiments. A.S. and A.B. wrote the manuscript. All authors discussed results, and provided input and edits on the manuscript. The authors declare no competing interests. Peer review information. Nature thanks Ania Majewska and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Group:Tianqiao and Chrissy Chen Institute for Neuroscience
Funding AgencyGrant Number
NIHDP2 MH100012-01
Robin Chemers Neustein AwardUNSPECIFIED
Robert A. Welch FoundationAQ-1507
National Alliance for Research on Schizophrenia and Depression25065
NIH Predoctoral FellowshipT32AG049688
NIH Predoctoral FellowshipT32AI078892
NIH Predoctoral FellowshipT32CA207201
Tianqiao and Chrissy Chen Institute for NeuroscienceUNSPECIFIED
Agency for Science, Technology and Research (A*STAR)UNSPECIFIED
CZI Neurodegeneration Challenge NetworkUNSPECIFIED
Vanderbilt UniversityUNSPECIFIED
Brain and Behavior Research FoundationUNSPECIFIED
Whitehall FoundationUNSPECIFIED
Edward Mallinckrodt, Jr. FoundationUNSPECIFIED
Issue or Number:7829
Record Number:CaltechAUTHORS:20200817-140210217
Persistent URL:
Official Citation:Badimon, A., Strasburger, H.J., Ayata, P. et al. Negative feedback control of neuronal activity by microglia. Nature 586, 417–423 (2020).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104985
Deposited By: George Porter
Deposited On:02 Oct 2020 23:46
Last Modified:16 Nov 2021 18:38

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