Negative feedback control of neuronal activity by microglia

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 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.

Reply to Green and Hume: Nonmicroglia peripheral immune effects of short-term CSF1R inhibition with PLX5622

“…We reject the comment by Green and Hume ( 4 ) that PLX5622 dose and duration was not provided or that it was selected arbitrarily. A careful reading of our paper ( 1 ) and the literature reveals this information, which is in concordance with at least 14 papers using exactly the same dose (PLX5622 chow, 1,200 ppm) and duration (3 wk) ( 1 – 3 , 5 ), some of which have been cited by Green et al ( 6 ) in a prior review. † For the benefit of the community, we provide additional data in this Reply showing that even short-term (7 d or 10 d) treatment with PLX5622 results in similar nonmicroglia changes ( Figs.…”

DJ-1 Regulates Microglial Polarization Through P62-Mediated TRAF6/IRF5 Signaling in Cerebral Ischemia-Reperfusion

“…The inflammatory response after cerebral ischemia-reperfusion (I/R) is characterized by the activation and polarization of resident microglia/macrophage ( Badimon et al, 2020 ), whose dynamic polarization state plays a dual role in brain injury and repair ( Kanazawa et al, 2017 ). Although there is controversy ( Ransohoff, 2016 ), it is generally believed that after stroke, microglia/macrophage are polarized into the pro-inflammatory (M1) phenotype and anti-inflammatory (M2) phenotype ( Yang et al, 2016 ).…”

Deficiency of Microglial Autophagy Increases the Density of Oligodendrocytes and Susceptibility to Severe Forms of Seizures

“…A growing body of evidence demonstrates that microglia influence neuronal excitability and seizure susceptibility ( Badimon et al, 2020 ; Umpierre et al, 2020 ; Wu et al, 2020 ). We found that excessive activation of mTOR in TSC1-deficient mice leads to severe spontaneous seizures, involving a noninflammatory mechanism ( Zhao et al, 2018 ).…”