Microglia stabilize sleep homeostasis via adenosine A3 receptor signaling
Zhao, Z.; Gu, X.; Yu, J.; Chen, X.; Zhang, L.; Zhao, T.; Ye, W.; Cheng, H.
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Sleep homeostasis maintains the sleep-wake balance through sleep pressure, a process orchestrated by the accumulation of extracellular adenosine (eADO). Microglial Ca{superscript 2} activity has been implicated in sleep regulation, but the mechanism whereby microglia sense sleep pressure remains unclear. Here we show that microglia regulate sleep homeostasis through brain state-dependent Ca2+ activity driven by adenosine A3 receptor (A3R) signaling. Using miniaturized two-photon microscopy (mTPM) in freely behaving mice, we demonstrate that microglial Ca{superscript 2} activity is rapidly altered by brain-state transitions. Pharmacological experiments reveal that microglial Ca2+ dynamics are predominantly mediated by A3R in response to brain state-dependent eADO oscillations. Microglia-specific deletion of A3R attenuates these state-dependent Ca2+ dynamics, impairs microglial morphological plasticity across sleep-wake cycles, and leads to sleep fragmentation by increasing transitions between wakefulness and non-rapid eye movement (NREM) sleep. Together, these findings establish that microglia regulate sleep homeostasis by stabilizing both wakefulness and NREM sleep, a process critically dependent on eADO-A3R signaling.
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