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. Robson, Wolfgang G. Junger, Robert Sebra, Erin S. Calipari, Paul J. Kenny, Ukpong B. Eyo, Marco Colonna, Francisco J. Quintana, Hiroaki Wake, Viviana Gradinaru and Anne Schaefer ()
Additional contact information
Ana Badimon: Icahn School of Medicine at Mount Sinai
Hayley J. Strasburger: Icahn School of Medicine at Mount Sinai
Pinar Ayata: Icahn School of Medicine at Mount Sinai
Xinhong Chen: California Institute of Technology
Aditya Nair: California Institute of Technology
Ako Ikegami: Nagoya University Graduate School of Medicine
Philip Hwang: Icahn School of Medicine at Mount Sinai
Andrew T. Chan: Icahn School of Medicine at Mount Sinai
Steven M. Graves: University of Minnesota
Joseph O. Uweru: University of Virginia
Carola Ledderose: Beth Israel Deaconess Medical Center, Harvard Medical School
Munir Gunes Kutlu: Vanderbilt University
Michael A. Wheeler: Brigham and Women’s Hospital, Harvard Medical School
Anat Kahan: California Institute of Technology
Masago Ishikawa: Icahn School of Medicine at Mount Sinai
Ying-Chih Wang: Icahn Institute of Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai
Yong-Hwee E. Loh: Icahn School of Medicine at Mount Sinai
Jean X. Jiang: University of Texas Health Science Center
D. James Surmeier: Northwestern University
Simon C. Robson: Beth Israel Deaconess Medical Center and Harvard Medical School
Wolfgang G. Junger: Beth Israel Deaconess Medical Center, Harvard Medical School
Robert Sebra: Icahn Institute of Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai
Erin S. Calipari: Vanderbilt University
Paul J. Kenny: Icahn School of Medicine at Mount Sinai
Ukpong B. Eyo: University of Virginia
Marco Colonna: Washington University School of Medicine
Francisco J. Quintana: Brigham and Women’s Hospital, Harvard Medical School
Hiroaki Wake: Nagoya University Graduate School of Medicine
Viviana Gradinaru: California Institute of Technology
Anne Schaefer: Icahn School of Medicine at Mount Sinai

Nature, 2020, vol. 586, issue 7829, 417-423

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2777-8

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