A circadian clock in the blood-brain barrier regulates xenobiotic efflux from the brain

Abstract

HighlightsO_LIThe Drosophila BBB displays a circadian rhythm of permeability\nC_LIO_LICyclic efflux driven by a clock in the BBB underlies the permeability rhythm\nC_LIO_LICircadian control is non-cell-autonomous via gap junction regulation of [Mg2+]i\nC_LIO_LIAn anti-seizure drug is more effective when administered at night\nC_LI\n\nSummaryEndogenous circadian rhythms are thought to modulate responses to external factors, but mechanisms that confer time-of-day differences in organismal responses to environmental insults / therapeutic treatments are poorly understood. Using a xenobiotic, we find that permeability of the Drosophila \"blood\"-brain barrier (BBB) is higher at night. The permeability rhythm is driven by circadian regulation of efflux and depends upon a molecular clock in the perineurial glia of the BBB, although efflux transporters are restricted to subperineurial glia (SPG). We show that transmission of circadian signals across the layers requires gap junctions, which are expressed cyclically. Specifically, during nighttime gap junctions reduce intracellular magnesium ([Mg2+]i), a positive regulator of efflux, in SPG. Consistent with lower nighttime efflux, nighttime administration of the anti-epileptic phenytoin is more effective at treating a Drosophila seizure model. These findings identify a novel mechanism of circadian regulation and have therapeutic implications for drugs targeted to the central nervous system.