Differential effects of P2Y12 inhibition on sleep and glymphatic function in male and female mice

Microglial P2Y12 receptor is a key regulator of neuroimmune homeostasis, but its role in integrating sleep, glymphatic influx, and microglial dynamics across sexes remains to be further investigated. In this study, we employed the P2Y12 antagonist MRS2395 for pharmacological inhibition in adult male and female C57BL/6 J mice. We assessed glymphatic influx, microglial density and morphology across multiple brain regions, sleep architecture via EEG, and behavioral outcomes. P2Y12 blockade disrupted sleep-stage glymphatic influx, microglial parameters, and sleep architecture, with the greater effects observed in females, particularly a greater suppression of glymphatic influx during sleep and more severe sleep fragmentation, characterized by increased state transitions and altered spectral power. In both sexes, P2Y12 inhibition reduced microglial branching complexity. Locomotor activity, cognitive performance, and anxiety-like behaviors did not differ significantly between the two sexes. These results preliminarily suggest that the microglial P2Y12 receptor pathway exerts sex-differential effects on glymphatic influx and sleep architecture during the rest phase, behavioral effects occurred but did not significantly differ between sexes in the short term.