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Cell. 2018 Mar 22;173(1):130-139.e10. doi: 10.1016/j.cell.2018.02.017. Epub 2018 Mar 8.

A Circadian Clock in the Blood-Brain Barrier Regulates Xenobiotic Efflux.

Author information

1
Center for Sleep and Circadian Neurobiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Chronobiology Program at Penn and Howard Hughes Medical Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Chronobiology Program at Penn and Howard Hughes Medical Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Center for Sleep and Circadian Neurobiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Chronobiology Program at Penn and Howard Hughes Medical Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: amita@pennmedicine.upenn.edu.

Abstract

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 on 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 cyclically expressed gap junctions. 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.

KEYWORDS:

Drosophila; blood-brain barrier; circadian rhythm; gap junction; perineurial glia; subperineurial glia; xenobiotic efflux

PMID:
29526461
PMCID:
PMC5866247
[Available on 2019-03-22]
DOI:
10.1016/j.cell.2018.02.017
[Indexed for MEDLINE]

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