2. Academic Validation
  3. Negative feedback control of neuronal activity by microglia

Negative feedback control of neuronal activity by microglia

  • Nature. 2020 Oct;586(7829):417-423. doi: 10.1038/s41586-020-2777-8.
Ana Badimon 1 2 3,  Hayley J Strasburger 1 2 3,  Pinar Ayata 1 2 3 4,  Xinhong Chen 5,  Aditya Nair 5,  Ako Ikegami 6 7,  Philip Hwang 1 2 3,  Andrew T Chan 1 2 3,  Steven M Graves 8,  Joseph O Uweru 9,  Carola Ledderose 10,  Munir Gunes Kutlu 11,  Michael A Wheeler 12,  Anat Kahan 5,  Masago Ishikawa 1,  Ying-Chih Wang 13,  Yong-Hwee E Loh 1,  Jean X Jiang 14,  D James Surmeier 15,  Simon C Robson 16 17,  Wolfgang G Junger 10,  Robert Sebra 13,  Erin S Calipari 11 18 19 20 21,  Paul J Kenny 1,  Ukpong B Eyo 9,  Marco Colonna 22,  Francisco J Quintana 12 23,  Hiroaki Wake 6 7,  Viviana Gradinaru 5,  Anne Schaefer 24 25 26 27
Affiliations

Affiliations

  • 1 Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3 Center for Glial Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4 Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
  • 6 Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 7 Division of System Neuroscience, Kobe University Graduate School of Medicine, Kobe, Japan.
  • 8 Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
  • 9 Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
  • 10 Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 11 Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
  • 12 Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 13 Department of Genetics and Genomic Sciences, Icahn Institute of Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 14 Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
  • 15 Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 16 Department of Anesthesia, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • 17 Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • 18 Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA.
  • 19 Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA.
  • 20 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
  • 21 Department of Psychiatry and Behavioral Sciences, Vanderbilt University, Nashville, TN, USA.
  • 22 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  • 23 The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 24 Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. anne.schaefer@mssm.edu.
  • 25 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. anne.schaefer@mssm.edu.
  • 26 Center for Glial Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. anne.schaefer@mssm.edu.
  • 27 Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA. anne.schaefer@mssm.edu.
PMID: 32999463 DOI: 10.1038/s41586-020-2777-8
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.

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