title: Chronic intermittent alcohol disrupts the GluN2B-associated proteome and specifically regulates group I mGlu receptor-dependent long-term depression.
abstract: N-Methyl-d-aspartate receptors (NMDARs) are major targets of both acute and chronic alcohol, as well as regulators of plasticity in a number of brain regions. Aberrant plasticity may contribute to the treatment resistance and high relapse rates observed in alcoholics. Recent work suggests that chronic alcohol treatment preferentially modulates both the expression and subcellular localization of NMDARs containing the GluN2B subunit. Signaling through synaptic and extrasynaptic GluN2B-NMDARs has already been implicated in the pathophysiology of various other neurological disorders. NMDARs interact with a large number of proteins at the glutamate synapse, and a better understanding of how alcohol modulates this proteome is needed. We employed a discovery-based proteomic approach in subcellular fractions of hippocampal tissue from chronic intermittent alcohol (CIE)-exposed C57Bl/6J mice to gain insight into alcohol-induced changes in GluN2B signaling complexes. Protein enrichment analyses revealed changes in the association of post-synaptic proteins, including scaffolding, glutamate receptor and PDZ-domain binding proteins with GluN2B. In particular, GluN2B interaction with metabotropic glutamate (mGlu)1/5receptor-dependent long-term depression (LTD)-associated proteins such as Arc and Homer 1 was increased, while GluA2 was decreased. Accordingly, we found a lack of mGlu1/5-induced LTD while α1-adrenergic receptor-induced LTD remained intact in hippocampal CA1 following CIE. These data suggest that CIE specifically disrupts mGlu1/5-LTD, representing a possible connection between NMDAR and mGlu receptor signaling. These studies not only demonstrate a new way in which alcohol can modulate plasticity in the hippocampus but also emphasize the utility of this discovery-based proteomic approach to generate new hypotheses regarding alcohol-related mechanisms.
authors.affiliation: Department of Molecular Physiology & Biophysics.|Department of Cell Biology & Anatomy, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Wills
authors.affiliation: Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Baucum
authors.affiliation: Vanderbilt Brain Institute.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Holleran
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Yaoyi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Molecular Physiology & Biophysics.
authors.forename: Johanna G
authors.initials: JG
authors.lastname: Pasek
authors.affiliation: Department of Molecular Physiology & Biophysics.|Vanderbilt Brain Institute.|J.F. Kennedy Center for Research on Human Development.|Department of Anesthesiology.
authors.forename: Eric
authors.initials: E
authors.lastname: Delpire
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Tabb
authors.affiliation: Department of Molecular Physiology & Biophysics.|Vanderbilt Brain Institute.|J.F. Kennedy Center for Research on Human Development.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
authors.affiliation: Department of Molecular Physiology & Biophysics.|Vanderbilt Brain Institute.|J.F. Kennedy Center for Research on Human Development.
authors.forename: Danny G
authors.initials: DG
authors.lastname: Winder
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D000072233:Homer Scaffolding Proteins / Q000187:drug effects / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D020543:Proteome / Q000187:drug effects / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002492:Central Nervous System Depressants; D003598:Cytoskeletal Proteins; D000072233:Homer Scaffolding Proteins; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D020543:Proteome; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C092069:activity regulated cytoskeletal-associated protein; D000431:Ethanol
keywords: Alcohol addiction; NMDA receptor; proteomics; synaptic plasticity