title: Mpdz expression in the caudolateral substantia nigra pars reticulata is crucially involved in alcohol withdrawal.
abstract: Association studies implicate the multiple PDZ domain protein (MUPP1/MPDZ) gene in risk for alcoholism in humans and alcohol withdrawal in mice. Although manipulation of the Mpdz gene by homologous recombination and bacterial artificial chromosome transgenesis has suggested that its expression affects alcohol withdrawal risk, the potential confounding effects of linked genes and developmental compensation currently limit interpretation. Here, using RNA interference (RNAi), we directly test the impact of Mpdz expression on alcohol withdrawal severity and provide brain regional mechanistic information. Lentiviral-mediated delivery of Mpdz short hairpin RNA (shRNA) to the caudolateral substantia nigra pars reticulata (clSNr) significantly reduces Mpdz expression and exacerbates alcohol withdrawal convulsions compared with control mice that delivered a scrambled shRNA. Neither baseline nor pentylenetetrazol-enhanced convulsions differed between Mpdz shRNA and control animals, indicating Mpdz expression in the clSNr does not generally affect seizure susceptibility. To our knowledge, these represent the first in vivo Mpdz RNAi analyses, and provide the first direct evidence that Mpdz expression impacts behavior. Our results confirm that Mpdz is a quantitative trait gene for alcohol withdrawal and demonstrate that its expression in the clSNr is crucially involved in risk for alcohol withdrawal.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA; Department of Veterans Affairs Medical Center, Oregon Health & Science University, Portland, OR, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Kruse
authors.forename: N A R
authors.initials: NA
authors.lastname: Walter
authors.forename: K J
authors.initials: KJ
authors.lastname: Buck
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D000431:Ethanol / Q000009:adverse effects*; D020022:Genetic Predisposition to Disease; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008811:Mice, Inbred DBA; D065841:Pars Reticulata / Q000378:metabolism*; D010641:Phenotype; D040641:Quantitative Trait Loci; D034622:RNA Interference; D013375:Substance Withdrawal Syndrome / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C491750:Mpdz protein, mouse; D000431:Ethanol
keywords: Alcohol; HICs; MUPP1; Mpdz; RNA interference; genetics; lentivirus; mouse; substantia nigra; withdrawal
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