Prostaglandin D₂ Controls Local Blood Flow and Sleep-Promoting Neurons in the VLPO via Astrocyte-Derived Adenosine

Abstract

Prostaglandin D₂ (PGD₂) is one of the most potent endogenous sleep-promoting molecules. However, the cellular and molecular mechanisms of the PGD₂-induced activation of sleep-promoting neurons in the ventrolateral preoptic nucleus (VLPO), the major nonrapid eye movement (NREM)-sleep center, still remains unclear. We here show that PGD₂ receptors (DP₁) are not only expressed in the leptomeninges but also in astrocytes from the VLPO. We further demonstrate, by performing real-time measurements of extracellular adenosine using purine enzymatic biosensors in the VLPO, that PGD₂ application causes a 40% increase in adenosine level, via an astroglial release. Measurements of vasodilatory responses and electrophysiological recordings finally reveal that, in response to PGD₂ application, adenosine release induces an A_2AR-mediated dilatation of blood vessels and activation of VLPO sleep-promoting neurons. Altogether, our results unravel the PGD₂ signaling pathway in the VLPO, controlling local blood flow and sleep-promoting neurons, via astrocyte-derived adenosine.