Journal Article

Negative feedback control of neuronal activity by microglia

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

2020

Overview

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 survival 1 . 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 A 1 R 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. Microglia, the brain’s immune cells, suppress neuronal activity in response to synaptic ATP release and alter behavioural responses in mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14/32 / 14/63 / 38 / 38/90 / 38/91 / 5'-Nucleotidase - metabolism / 631/378/2596/1953 / 631/378/371 / 64/60 / 82/51 / 82/80 / Ablation / Acids / Action Potentials / Adenosine / Adenosine - metabolism / Adenosine diphosphate / Adenosine Monophosphate - metabolism / Adenosine Triphosphate - metabolism / AMP / Animal behavior / Animals / Antigens, CD - metabolism / Apyrase - metabolism / Astrocytes / ATP / Biofeedback training / Brain / Calcium - metabolism / CD73 antigen / Corpus Striatum - cytology / Corpus Striatum - physiology / Feedback / Feedback (Psychology) / Feedback control / Feedback, Physiological / Female / Gene expression / Humanities and Social Sciences / Humans / Macrophages / Male / Mice / Mice, Inbred C57BL / Microglia / Microglia - cytology / Microglia - physiology / Modulators / Motility / multidisciplinary / Negative feedback / Neural circuitry / Neural Inhibition - genetics / Neurological research / Neuromodulation / Neurons / Neurons - physiology / Physiological aspects / Receptor, Adenosine A1 - metabolism / Receptor, Muscarinic M3 - genetics / Receptor, Muscarinic M3 - metabolism / Science / Science (multidisciplinary) / Seizures / Synapses / Time Factors