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bioRxiv · 10.64898/2026.01.02.697450

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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Abstract

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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Zhao, Z., Gu, X., Yu, J., Chen, X., Zhang, L., Zhao, T., Ye, W., Cheng, H.. 2026-01-03. Microglia stabilize sleep homeostasis via adenosine A3 receptor signaling. https://doi.org/10.64898/2026.01.02.697450

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