RT Journal Article
SR Electronic
T1 A circadian clock in the blood-brain barrier regulates xenobiotic efflux from the brain
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 196956
DO 10.1101/196956
A1 Zhang, Shirley L.
A1 Yue, Zhifeng
A1 Arnold, Denice M.
A1 Sehgal, Amita
YR 2017
UL http://biorxiv.org/content/early/2017/10/04/196956.abstract
AB HighlightsThe Drosophila BBB displays a circadian rhythm of permeabilityCyclic efflux driven by a clock in the BBB underlies the permeability rhythmCircadian control is non-cell-autonomous via gap junction regulation of [Mg2+]iAn anti-seizure drug is more effective when administered at nightSummary Endogenous 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.