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Opposite actions of alcohol on tonic GABAA receptor currents mediated by nNOS and PKC activity

Nature Neuroscience volume 16, pages 1783–1793 (2013)Cite this article

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Abstract

The molecular mechanisms that mediate genetic variability in response to alcohol are unclear. We found that alcohol had opposite actions (enhancement or suppression) on GABAA receptor (GABAAR) inhibition in granule cells from the cerebellum of behaviorally sensitive, low alcohol–consuming Sprague-Dawley rats and DBA/2 mice and behaviorally insensitive, high alcohol–consuming C57BL/6 mice, respectively. The effect of alcohol on granule cell GABAAR inhibition was determined by a balance between two opposing effects: enhanced presynaptic vesicular release of GABA via alcohol inhibition of nitric oxide synthase (NOS) and a direct suppression of the activity of postsynaptic GABAARs. The balance of these two processes was determined by differential expression of neuronal NOS (nNOS) and postsynaptic PKC activity, both of which varied across the rodent genotypes. These findings identify opposing molecular processes that differentially control the magnitude and polarity of GABAAR responses to alcohol across rodent genotypes.

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Figure 1: C57BL/6J and DBA/2J mouse granule cells exhibit similar magnitude tonic currents mediated by α6 and δ subunit–containing GABAARs.
Figure 2: The effect of ethanol on granule cell tonic GABAAR currents varies in polarity and magnitude across rodent genotypes with divergent ethanol consumption phenotypes.
Figure 3: Ethanol-induced potentiation of granule cell tonic GABAAR current is mediated by suppression of NOS and consequent increase in action potential dependent vesicular release of GABA.
Figure 4: Ethanol suppresses tonic production of NO in the granule cell layer.
Figure 5: Ethanol inhibition of NOS increases Golgi cell firing.
Figure 6: Differential expression of nNOS underlies differences in ethanol-induced potentiation of granule cell GABAAR transmission.
Figure 7: Ethanol-induced suppression of tonic GABAAR current in C57BL/6J and DBA/2J granule cells is a result of direct action on GABAARs.
Figure 8: Direct suppression of tonic GABAAR current by ethanol is prevented by postsynaptic PKC activity.

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Acknowledgements

We thank J. Crabbe, D. Finn and K. Wiren (Oregon Health and Science University) for discussions about the research and D. Attwell (University College London) for comments on the manuscript. This study was supported by National Institute of Neurological Disorders and Stroke grant R01NS051561, National Institute on Alcohol Abuse and Alcoholism grant R01AA012439, an American Heart Association Grant in Aid, and a Medical Research Foundation of Oregon grant to D.J.R., training grants T32 AA007468 and F31 AA022267 from the National Institute on Alcohol Abuse and Alcoholism, and an Oregon Health and Science University Research Scholars Award to J.S.K., and the Neuroscience Imaging Center at Oregon Health and Science University grant P30NS061800 from the National Institute of Neurological Disorders and Stroke.

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  1. Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon, USA

    Joshua S Kaplan, Claudia Mohr & David J Rossi

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  1. Joshua S Kaplan
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Contributions

J.S.K. and D.J.R. designed the experiments. J.S.K. performed the electrophysiology experiments and C.M. performed the immunocytochemistry experiments. J.S.K. and D.J.R. analyzed the data and wrote the manuscript.

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Correspondence to David J Rossi.

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Kaplan, J., Mohr, C. & Rossi, D. Opposite actions of alcohol on tonic GABAA receptor currents mediated by nNOS and PKC activity. Nat Neurosci 16, 1783–1793 (2013). https://doi.org/10.1038/nn.3559

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