Exploring the mechanisms of microglia activation has revealed insights into the interconnections of the immune system and brain. Huang et al. demonstrate that the complex of sodium/potassium-transporting ATPase subunit alpha (NKAa1) and purinergic P2X7 receptor (P2X7R) maintains the resting state of microglial membranes. Stress increases free P2X7R that then binds to ATP to activate microglia, which may promote anxious behaviors.