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Molecular Pharmacology

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Research ArticleArticle

Plasticity of GABAA Receptors after Ethanol Pre-Exposure in Cultured Hippocampal Neurons

Yi Shen, A. Kerstin Lindemeyer, Igor Spigelman, Werner Sieghart, Richard W. Olsen and Jing Liang
Molecular Pharmacology March 2011, 79 (3) 432-442; DOI: https://doi.org/10.1124/mol.110.068650
Yi Shen
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A. Kerstin Lindemeyer
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Igor Spigelman
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Werner Sieghart
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Richard W. Olsen
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Jing Liang
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Abstract

Alcohol use causes many physiological changes in brain with behavioral sequelae. We previously observed (J Neurosci 27:12367–12377, 2007) plastic changes in hippocampal slice recordings paralleling behavioral changes in rats treated with a single intoxicating dose of ethanol (EtOH). Here, we were able to reproduce in primary cultured hippocampal neurons many of the effects of in vivo EtOH exposure on GABAA receptors (GABAARs). Cells grown 11 to 15 days in vitro demonstrated GABAAR δ subunit expression and sensitivity to enhancement by short-term exposure to EtOH (60 mM) of GABAAR-mediated tonic current (Itonic) using whole-cell patch-clamp techniques. EtOH gave virtually no enhancement of mIPSCs. Cells pre-exposed to EtOH (60 mM) for 30 min showed, 1 h after EtOH withdrawal, a 50% decrease in basal Itonic magnitude and tolerance to short-term EtOH enhancement of Itonic, followed by reduced basal mIPSC area at 4 h. At 24 h, we saw considerable recovery in mIPSC area and significant potentiation by short-term EtOH; in addition, GABAAR currents exhibited reduced enhancement by benzodiazepines. These changes paralleled significant decreases in cell-surface expression of normally extrasynaptic δ and α4 GABAAR subunits as early as 20 min after EtOH exposure and reduced α5-containing GABAARs at 1 h, followed by a larger reduction of normally synaptic α1 subunit at 4 h, and then by increases in α4γ2-containing cell-surface receptors by 24 h. Measuring internalization of biotinylated GABAARs, we showed for the first time that the EtOH-induced loss of Itonic and cell-surface δ/α4 20 min after withdrawal results from increased receptor endocytosis rather than decreased exocytosis.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grants AA07680, AA017991, AA016100].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.068650.

  • ABBREVIATIONS:

    GABAAR
    GABA type A receptor
    EtOH
    ethanol
    CA
    cornu ammonis
    DIV
    days in vitro
    Itonic
    tonic current
    mIPSCs
    miniature inhibitory postsynaptic currents
    PBS
    phosphate-buffered saline
    ANOVA
    analysis of variance.

  • Received September 3, 2010.
  • Accepted December 15, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (3)
Molecular Pharmacology
Vol. 79, Issue 3
1 Mar 2011
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Research ArticleArticle

Plasticity of GABAA Receptors after Ethanol Pre-Exposure in Cultured Hippocampal Neurons

Yi Shen, A. Kerstin Lindemeyer, Igor Spigelman, Werner Sieghart, Richard W. Olsen and Jing Liang
Molecular Pharmacology March 1, 2011, 79 (3) 432-442; DOI: https://doi.org/10.1124/mol.110.068650

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Research ArticleArticle

Plasticity of GABAA Receptors after Ethanol Pre-Exposure in Cultured Hippocampal Neurons

Yi Shen, A. Kerstin Lindemeyer, Igor Spigelman, Werner Sieghart, Richard W. Olsen and Jing Liang
Molecular Pharmacology March 1, 2011, 79 (3) 432-442; DOI: https://doi.org/10.1124/mol.110.068650
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