GluN2B subunit deletion reveals key role in acute and chronic ethanol sensitivity of glutamate synapses in bed nucleus of the stria terminalis

Tiffany A. Wills, Jason R. Klug, Yuval Silberman, Anthony J. Baucum, Carl Weitlauf, Roger J. Colbran, Eric Delpire, Danny G. Winder

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Abstract

The bed nucleus of the stria terminalis (BNST) is a critical region for alcohol/drug-induced negative affect and stress-induced reinstatement. NMDA receptor (NMDAR)-dependent plasticity, such as longterm potentiation (LTP), has been postulated to play key roles in alcohol and drug addiction; yet, to date, little is understood regarding the mechanisms underlying LTP of the BNST, or its regulation by ethanol. Acute and chronic exposure to ethanol modulates glutamate transmission via actions on NMDARs. Despite intense investigation, tests of subunit specificity of ethanol actions on NMDARs using pharmacological approaches have produced mixed results. Thus, we use a conditional GluN2B KO mouse line to assess both basal and ethanol-dependent function of this subunit at glutamate synapses in the BNST. Deletion of GluN2B eliminated LTP, as well as actions of ethanol on NMDAR function. Further, we show that chronic ethanol exposure enhances LTP formation in the BNST. Using KO-validated pharmacological approaches with Ro25-6981 and memantine, we provide evidence suggesting that chronic ethanol exposure enhances LTP in the BNST via paradoxical extrasynaptic NMDAR involvement. These findings demonstrate that GluN2B is a key point of regulation for ethanol's actions and suggest a unique role of extrasynaptic GluN2B-containing receptors in facilitating LTP.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number5
DOIs
StatePublished - Jan 31 2012

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Septal Nuclei
Synapses
Glutamic Acid
Ethanol
N-Methyl-D-Aspartate Receptors
Pharmacology
Memantine
Alcoholism
Substance-Related Disorders
Alcohols

All Science Journal Classification (ASJC) codes

  • General

Cite this

Wills, Tiffany A. ; Klug, Jason R. ; Silberman, Yuval ; Baucum, Anthony J. ; Weitlauf, Carl ; Colbran, Roger J. ; Delpire, Eric ; Winder, Danny G. / GluN2B subunit deletion reveals key role in acute and chronic ethanol sensitivity of glutamate synapses in bed nucleus of the stria terminalis. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 5.
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GluN2B subunit deletion reveals key role in acute and chronic ethanol sensitivity of glutamate synapses in bed nucleus of the stria terminalis. / Wills, Tiffany A.; Klug, Jason R.; Silberman, Yuval; Baucum, Anthony J.; Weitlauf, Carl; Colbran, Roger J.; Delpire, Eric; Winder, Danny G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 5, 31.01.2012.

Research output: Contribution to journalArticle

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AU - Silberman, Yuval

AU - Baucum, Anthony J.

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