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.