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A new naturally occurring GABAA receptor subunit partnership with high sensitivity to ethanol

Abstract

According to the rules of GABAA receptor (GABAAR) subunit assembly, α4 and α6 subunits are considered to be the natural partners of δ subunits. These GABAARs are a preferred target of low, sobriety-impairing concentrations of ethanol. Here we demonstrate a new naturally occurring GABAAR subunit partnership: δ subunits of hippocampal interneurons are coexpressed and colocalized with α1 subunits, but not with α4, α6 or any other α subunits. Ethanol potentiates the tonic inhibition mediated by such native α1/δ GABAARs in wild-type and in α4 subunit–deficient (Gabra4−/−) mice, but not in δ subunit–deficient (Gabrd−/−) mice. We also ruled out any compensatory upregulation of α6 subunits that might have accounted for the ethanol effect in Gabra4−/− mice. Thus, α1/δ subunit assemblies represent a new neuronal GABAAR subunit partnership present in hippocampal interneurons, mediate tonic inhibitory currents and are highly sensitive to low concentrations of ethanol.

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Figure 1: Distribution of α1, α4 and δ GABAAR subunits in ML interneurons and the properties of phasic and tonic inhibitions.
Figure 2: α1, but not other α subunits, is strongly expressed on the surface of interneurons in the dentate ML.
Figure 3: Ethanol potentiates the tonic inhibition in wild-type (WT) but not in GABAAR δ subunit–null mutant (Gabrd−/−) ML interneurons.
Figure 4: Comparison of α4 and δ subunit labeling in the dentate gyrus of wild-type (WT) and Gabra4−/− mice.
Figure 5: Potential colocalization of the α1 subunit and δ subunits in ML interneurons of Gabra4−/− mice.
Figure 6: Ethanol-induced potentiation of tonic inhibition in ML interneurons persists in mice lacking the α4 GABAAR subunit (Gabra4−/−).
Figure 7: Lack of compensatory upregulation of α6 subunits in ML interneurons of mice lacking α4 GABAAR subunits.

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Acknowledgements

We thank W. Sieghart (Medical Univ. of Vienna, Austria) and J.-M. Fritschy (Univ. Zürich, Switzerland) for the gifts of the GABAAR antibodies, and R.W. Olsen (UCLA) for helpful discussions. This project was supported by the Gonda Fellowship awarded to J. G., US National Institutes of Health (NIH) Grants NS30549, NS35958 and the Coelho Endowment to I. M., NIH Grant NS051311 and US Veterans Administration Medical Research Funds to C.R.H., and NIH Grant AA14003 to G.E.H.

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Authors and Affiliations

Authors

Contributions

J.G. performed the electrophysiology, Z.P. carried out the immunohistochemistry, and D.C. and G.E.H. produced the Gabra4−/− mice. J.G., Z.P., C.R.H. and I.M. carried out the data analysis, study conceptualization and figure preparation. J.G., C.R.H. and I.M. wrote and edited the manuscript. G.E.H. provided comments on the manuscript, and G.E.H., C.R.H. and I.M. provided financial support.

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Correspondence to Istvan Mody.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

GAD67-labeled interneurons in the molecular layer consistently express the α1 subunit (Row a), and virtually all α1-labeled interneurons express the δ subunit (Row b). (PDF 6737 kb)

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Glykys, J., Peng, Z., Chandra, D. et al. A new naturally occurring GABAA receptor subunit partnership with high sensitivity to ethanol. Nat Neurosci 10, 40–48 (2007). https://doi.org/10.1038/nn1813

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