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Modulation of GABAA receptor desensitization uncouples sleep onset and maintenance in Drosophila

Nature Neuroscience volume 11, pages 354–359 (2008)Cite this article

Abstract

Many lines of evidence indicate that GABA and GABAA receptors make important contributions to human sleep regulation. Pharmacological manipulation of these receptors has differential effects on sleep onset and sleep maintenance insomnia. Here we show that sleep is regulated by GABA in Drosophila and that a mutant GABAA receptor, RdlA302S, specifically decreases sleep latency. The drug carbamazepine (CBZ) has the opposite effect on sleep; it increases sleep latency as well as decreasing sleep. Behavioral and physiological experiments indicated that RdlA302S mutant flies are resistant to the effects of CBZ on sleep latency and that mutant RDLA302S channels are resistant to the effects of CBZ on desensitization, respectively. These results suggest that this biophysical property of the channel, specifically channel desensitization, underlies the regulation of sleep latency in flies. These experiments uncouple the regulation of sleep latency from that of sleep duration and suggest that the kinetics of GABAA receptor signaling dictate sleep latency.

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Figure 1: GABAergic neurons control sleep in Drosophila. Sleep parameters are shown for flies expressing a hyperpolarizing potassium channel (UAS-Shaw) under the control of GAD-GAL4. Single transgene sibling controls (UAS only and GAL4 only) are also shown.
Figure 2: RdlA302S flies show decreased sleep latency and increased sleep-episode duration.
Figure 3: CBZ markedly decreases fly sleep by increasing sleep latency and decreasing episode duration (a) Conventional sleep plot showing the effect of different concentrations of CBZ on the sleep pattern of wild-type (Canton-S) flies during the first day of drug treatment.
Figure 4: RdlA302S flies are resistant to CBZ effects on sleep latency, but not to its effects on sleep-episode duration.
Figure 5: The RdlA302S mutation rescues sleep homeostasis.
Figure 6: CBZ specifically increases RDL desensitization and the A302S mutation prevents CBZ effects (a) Response to 90-s application of 100 μM GABA with variable doses of CBZ, recorded from oocytes expressing RDL held at −60 mV under voltage clamp.

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Acknowledgements

We are grateful to E. Marder, R. Allada and R. Greenspan for comments on the manuscript. This work was funded by a grant from the US Army (W81XWH-04-1-0158) to M.R. and L.C.G., and MH 067284 to L.C.G.

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Author notes

  1. James C Choi

    Present address: Present address: Department of Neurology, Neurobiology Program, Children's Hospital, Boston, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.,

Authors and Affiliations

  1. Howard Hughes Medical Institute, Brandeis University, 415 South St., Waltham, 02454-9110, Massachusetts, USA

    Jose Agosto & Michael Rosbash

  2. Department of Biology, Brandeis University, 415 South St., Waltham, 02454-9110, Massachusetts, USA

    Jose Agosto, James C Choi, Katherine M Parisky, Michael Rosbash & Leslie C Griffith

  3. National Center for Behavioral Genomics, Brandeis University, 415 South St., Waltham, 02454-9110, Massachusetts, USA

    Jose Agosto, James C Choi, Katherine M Parisky, Michael Rosbash & Leslie C Griffith

  4. Cambria Biosciences, Woburn, 01801, Massachusetts, USA

    Geoffrey Stilwell

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Correspondence to Leslie C Griffith.

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Agosto, J., Choi, J., Parisky, K. et al. Modulation of GABAA receptor desensitization uncouples sleep onset and maintenance in Drosophila. Nat Neurosci 11, 354–359 (2008). https://doi.org/10.1038/nn2046

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