Gait Abnormalities and Aberrant D2 Receptor Expression and Signaling in a Mouse Model of the Human Pathogenic Mutation DRD2I212F

Abstract

AbstractA dopamine D2 receptor mutation was recently identified in a family with a novel hyperkinetic movement disorder (Mov Disord 36: 729-739, 2021). That allelic variant D2-I212F is a constitutively active and G protein-biased receptor. We now describe mice engineered to carry the D2-I212F variant, Drd2I212F. The mice exhibited gait abnormalities resembling those in other mouse models of chorea and/or dystonia, and had decreased striatal D2 receptor expression. Electrically evoked IPSCs in midbrain dopamine neurons and striatum from Drd2I212F mice exhibited slow onset and decay compared to wild type mice. In the presence of dopamine, current decay initiated by photolytic release of sulpiride from CyHQ-sulpiride was slower in midbrain slices from Drd2I212F mice than Drd2+/+ mice. Furthermore, in contrast to wild type mice in which dopamine is more potent at neurons in the nucleus accumbens than in the dorsal striatum, reflecting activation of Gαo vs. Gαi1, dopamine had similar potencies in those two brain regions of Drd2I212F mice. Repeated cocaine treatment, which decreases dopamine potency in the nucleus accumbens of wild type mice, had no effect on dopamine potency in Drd2I212F mice. The results demonstrate the utility of this mouse model for investigating the role of pathogenic DRD2 variants in early-onset hyperkinetic movement disorders.