Negative feedback control of neuronal activity by microglia

Microglia, the brain resident macrophages, play a key role in the regulation of brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival. We have identified a new function of microglia as critical modulators of neuronal activity and associated behavioral responses in mice. We show that microglia respond to neuronal activation and that ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. The suppressive impact of microglia on neuronal activation occurs in a highly localized fashion and depends on the ability of microglia to sense and catabolize extracellular ATP. ATP, which can be released upon neuronal activation by neurons and astrocytes, triggers the recruitment of microglia protrusions and is converted by the microglial ATP-hydrolyzing enzyme CD39 and CD73 into AMP and adenosine, a potent suppressor of neuronal activity. We show that the microglial sensing of ATP, the ensuing production of adenosine, and the adenosine-mediated control of neuronal response via the A1R are essential for the microglia-mediated regulation of neuronal activity and animal behavior. Our findings suggest that this microglia-driven negative feedback mechanism operates in a fashion similar to inhibitory neurons and plays an essential role in protecting the brain from excessive activation in health and diseases. Microglial or neuronal RNAs were isolated based on the eGFP-L10a expression of ribosomes. Single nuclei sequencing was performed on striatal nuclei using 10X technology.