Gait Abnormalities and Aberrant D2 Receptor Expression and Signaling in Mice Carrying the Human Pathogenic Mutation DRD2 I212F .

A 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-I 212 F is a constitutively active and G protein-biased receptor. We now describe mice engineered using CRISPR-Cas9-mediated gene editing technology to carry the D2-I 212 F variant, Drd2 I212F mice. The mice exhibited gait abnormalities resembling those in other mouse models of chorea and/or dystonia, and had striatal D2 receptor expression that was decreased ~30% per Drd2 I212F allele. Electrically evoked inhibitory postsynaptic conductances in midbrain dopamine neurons and striatum from Drd2 I212F mice, caused by G protein activation of potassium channels, exhibited slow kinetics (e.g., ~4-6 fold slower decay) compared to Drd2 +/+ mice. Current decay initiated by photolytic release of the D2 antagonist sulpiride from CyHQ-sulpiride was also ~4-fold slower in midbrain slices from Drd2 I212F mice than Drd2 +/+ mice. Furthermore, in contrast to Drd2 +/+ mice in which dopamine is several-fold more potent at neurons in the nucleus accumbens than in the dorsal striatum, reflecting activation of Ga o vs. Ga i , dopamine had similar potencies in those two brain regions of Drd2 I212F mice. Repeated cocaine treatment, which decreases dopamine potency in the nucleus accumbens of Drd2 +/+ mice, had no effect on dopamine potency in Drd2 I212F mice. The results demonstrate the pathogenicity of the D2-I 212 F mutation and the utility of this mouse model for investigating the role of pathogenic DRD2 variants in early-onset hyperkinetic movement disorders. Significance Statement We recently identified the first dopamine receptor mutation believed to cause a movement disorder, D2-I 212 F. The mutation makes receptor activation of G protein-mediated signaling more efficient. To confirm the pathogenesis of D2-I 212 F, we now report that mice carrying this mutation have gait abnormalities consistent with the clinical phenotype. The mutation also profoundly alters D2 receptor expression and function in vivo. This mouse model will be useful for further characterization of the mutant receptor and for evaluation of potential therapeutic drugs.