Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission

Sleep interacts reciprocally with immune system activity, but its specific relationship with microglia—the resident immune cells in the brain—remains poorly understood. Here, we show in mice that microglia can regulate sleep through a mechanism involving G i -coupled GPCRs, intracellular Ca 2+ signaling and suppression of norepinephrine transmission. Chemogenetic activation of microglia G i signaling strongly promoted sleep, whereas pharmacological blockade of G i -coupled P2Y12 receptors decreased sleep. Two-photon imaging in the cortex showed that P2Y12–G i activation elevated microglia intracellular Ca 2+ , and blockade of this Ca 2+ elevation largely abolished the G i -induced sleep increase. Microglia Ca 2+ level also increased at natural wake-to-sleep transitions, caused partly by reduced norepinephrine levels. Furthermore, imaging of norepinephrine with its biosensor in the cortex showed that microglia P2Y12–G i activation significantly reduced norepinephrine levels, partly by increasing the adenosine concentration. These findings indicate that microglia can regulate sleep through reciprocal interactions with norepinephrine transmission.