Negative feedback control of neuronal activity by microglia

Ana Badimon, Hayley J. Strasburger, Pinar Ayata, Xinhong Chen, Aditya Nair, Ako Ikegami, Philip Hwang, Andrew T. Chan, Steven M. Graves, Joseph O. Uweru, Carola Ledderose, Munir Gunes Kutlu, Michael A. Wheeler, Anat Kahan, Masago Ishikawa, Ying Chih Wang, Yong Hwee E. Loh, Jean X. Jiang, D. James Surmeier, Simon C. RobsonWolfgang G. Junger, Robert Sebra, Erin S. Calipari, Paul J. Kenny, Ukpong B. Eyo, Marco Colonna, Francisco J. Quintana, Hiroaki Wake, Viviana Gradinaru, Anne Schaefer

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)417-423
Number of pages7
JournalNature
Volume586
Issue number7829
DOIs
StatePublished - Oct 15 2020

Bibliographical note

Funding Information:
Acknowledgements We thank P. Greengard and A. Nairn for sharing the DARPP32 antibodies; J. J. Badimon for the Ticagrelor and Clopidogrel; R. Greene for the Adora1fl/fl mice; M. Merad and F. Desland for the Csf1fl/fl; NestinCre 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).

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