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Negative feedback control of neuronal activity by microglia. 2020
Ana Badimon, and
Hayley J Strasburger, and
Pinar Ayata, and
Xinhong Chen, and
Aditya Nair, and
Ako Ikegami, and
Philip Hwang, and
Andrew T Chan, and
Steven M Graves, and
Joseph O Uweru, and
Carola Ledderose, and
Munir Gunes Kutlu, and
Michael A Wheeler, and
Anat Kahan, and
Masago Ishikawa, and
Ying-Chih Wang, and
Yong-Hwee E Loh, and
Jean X Jiang, and
D James Surmeier, and
Simon C Robson, and
Wolfgang G Junger, and
Robert Sebra, and
Erin S Calipari, and
Paul J Kenny, and
Ukpong B Eyo, and
Marco Colonna, and
Francisco J Quintana, and
Hiroaki Wake, and
Viviana Gradinaru, and
Anne Schaefer
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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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