Negative feedback control of neuronal activity by microglia.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE

Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.

Feedback, Physiological* ; Neural Inhibition*/genetics; Microglia/*physiology ; Neurons/*physiology; 5'-Nucleotidase/metabolism ; Action Potentials ; Adenosine/metabolism ; Adenosine Monophosphate/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Antigens, CD/metabolism ; Apyrase/metabolism ; Calcium/metabolism ; Corpus Striatum/cytology ; Corpus Striatum/physiology ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/cytology ; Receptor, Adenosine A1/metabolism ; Receptor, Muscarinic M3/genetics ; Receptor, Muscarinic M3/metabolism ; Time Factors

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.

Comment in: Nature. 2020 Oct;586(7829):366-367. (PMID: 32999439)
Comment in: Purinergic Signal. 2020 Dec;16(4):477-478. (PMID: 33404957)
Comment in: Signal Transduct Target Ther. 2021 Apr 17;6(1):160. (PMID: 33866328)

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0 (Antigens, CD)
0 (Receptor, Adenosine A1)
0 (Receptor, Muscarinic M3)
415SHH325A (Adenosine Monophosphate)
8L70Q75FXE (Adenosine Triphosphate)
EC 3.1.3.5 (5'-Nucleotidase)
EC 3.6.1.5 (Apyrase)
EC 3.6.1.5 (CD39 antigen)
K72T3FS567 (Adenosine)
SY7Q814VUP (Calcium)

Date Created: 20201001 Date Completed: 20210114 Latest Revision: 20220716

20231215

PMC7577179

10.1038/s41586-020-2777-8

32999463