Mpdz expression in the caudolateral substantia nigra pars reticulata is crucially involved in alcohol withdrawal

L. C. Kruse, N. A R Walter, Kari Buck

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)769-776
Number of pages8
JournalGenes, Brain and Behavior
Volume13
Issue number8
DOIs
StatePublished - Nov 1 2014

Fingerprint

Alcohols
Small Interfering RNA
Seizures
RNA Interference
Genes
PDZ Domains
Developmental Genes
Bacterial Artificial Chromosomes
Gene Transfer Techniques
Pentylenetetrazole
Homologous Recombination
Alcoholism
Pars Reticulata
Brain
Proteins

Keywords

  • Alcohol
  • Genetics
  • HICs
  • Lentivirus
  • Mouse
  • Mpdz
  • MUPP1
  • RNA interference
  • Substantia nigra
  • Withdrawal

ASJC Scopus subject areas

  • Behavioral Neuroscience
  • Genetics
  • Neurology

Cite this

Mpdz expression in the caudolateral substantia nigra pars reticulata is crucially involved in alcohol withdrawal. / Kruse, L. C.; Walter, N. A R; Buck, Kari.

In: Genes, Brain and Behavior, Vol. 13, No. 8, 01.11.2014, p. 769-776.

Research output: Contribution to journalArticle

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