Gait Abnormalities and Aberrant D2 Receptor Expression and Signaling in Mice Carrying the Human Pathogenic Mutation DRD2I212F

Dayana Rodriguez-Contreras, Sheng Gong, Joseph J. Lebowitz, Lev M. Fedorov, Naeem Asad, Timothy M. Dore, Tamara J. Phillips, Christopher P. Ford, John T. Williams, Kim A. Neve

Research output: Contribution to journalArticlepeer-review

Abstract

A dopamine D2 receptor mutation was recently identified in a family with a novel hyperkinetic movement disorder. That allelic variant D2-I212F is a constitutively active and G protein-biased receptor. We now describe mice engineered using CRISPRCas9- mediated gene editing technology to carry the D2-I212 F variant. Drd2I212F mice exhibited gait abnormalities resembling those in othermousemodels of chorea and/or dystonia and had striatal D2 receptor expression that was decreased approximately 30% per Drd2I212F allele. Electrically evoked inhibitory postsynaptic conductances in midbrain dopamine neurons and striatumfromDrd2I212F mice, caused by G protein activation of potassium channels, exhibited slow kinetics (e.g., approximately four- to sixfold slower decay) compared with Drd21/1 mice. Current decay initiated by photolytic release of the D2 antagonist sulpiride from CyHQ-sulpiride was also _fourfold slower in midbrain slices from Drd2I212F mice than Drd21/1 mice. Furthermore, in contrast to Drd21/1 mice, in which dopamine is several-fold more potent at neurons in the nucleus accumbens than in the dorsal striatum, reflecting activation of Gao versus Gai, dopamine had similar potencies in those two brain regions of Drd2I212F mice. Repeated cocaine treatment, which decreases dopamine potency in the nucleus accumbens of Drd21/1 mice, had no effect on dopamine potency in Drd2I212F mice. The results demonstrate the pathogenicity of the D2-I212F mutation and the utility of thismousemodel for investigating the role of pathogenic DRD2 variants in early-onset hyperkinetic movement disorders.

Original languageEnglish (US)
Pages (from-to)188-198
Number of pages11
JournalMolecular pharmacology
Volume103
Issue number3
DOIs
StatePublished - Mar 1 2023

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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