Guardians of the Frequency: Neuronal Regulation by Microglia

Microglial G(i)-Dependent Dynamics Regulate Brain Network Hyperexcitability Merlini M, Rafalski VA, Ma K, et al. Nat Neurosci. 2021;24(1):19-23. doi:10.1038/s41593-020-00756-7Microglial surveillance is a key feature of brain physiology and disease. Here, we found that Gi-dependent microglial dynamics prevent neuronal network hyperexcitability. By generating MgPTX mice to genetically inhibit Gi in microglia, we show that sustained reduction in microglia brain surveillance and directed process motility-induced spontaneous seizures and increased hypersynchrony after physiologically evoked neuronal activity in awake adult mice. Thus, Gi-dependent microglia dynamics may prevent hyperexcitability in neurological diseases. Negative Feedback Control of Neuronal Activity by Microglia Badimon A, Strasburger HJ, Ayata P, et al. Nature. 2020;586(7829):417-423. doi:10.1038/s41586-020-2777-8Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning nonfunctional synapses, and producing ligands that support neuronal survival. 1 Here, we show that microglia are also critical modulators of neuronal activity and associated behavioral 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 adenosine triphosphate (ATP), which is released upon neuronal activation by neurons and astrocytes. Adenosine triphosphate 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 and 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 behavior. 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.