Mice carrying the human dopamine D2 receptor pathogenic mutation p.Met374Arg exhibit hyperactivity and aberrant D2 receptor function.

Abstract

Two human dopamine D2 receptor mutations cause dominant hyperkinetic movement disorders. The phenotype of carriers of the DRD2 variant c.634A>T, p.Ile212Phe (D2-I212F) is less severe than that of carriers of the variant c.1121 T>G, p.Met374Arg (D2-M^6.36R). Both are gain-of-function mutations with respect to G protein-mediated signaling; however, D2-M^6.36R exhibits greater gain-of-function than D2-I212F, suggesting that this is a major contributor to pathogenicity. Drd2^I212F knock-in mice exhibit altered D2 receptor function consistent with the clinical phenotype. We now report that mice carrying the mutation D2-M^6.36R, Drd2^M6.36R knock-in mice, exhibited gait abnormalities and a 2-fold increase in locomotor activity, and females fell more quickly from an accelerating rotarod. Electrically evoked inhibitory postsynaptic conductances in midbrain dopamine neurons from heterozygous Drd2^M6.36R mice were prolonged compared with both Drd2^I212F and wild-type (WT) mice. Electrically evoked release of acetylcholine and dopamine was similar in neostriatal slices from Drd2^M6.36R, Drd2^I212F, and WT mice. Inhibition of acetylcholine release by the D2 receptor agonist quinpirole was decreased by approximately 25% relative to WT mice in slices from either heterozygous knock-in mouse, whereas reversal by sulpiride was reduced by approximately 40% only in Drd2^M6.36R+/- mice. Although the postsynaptic current measured in dopamine cell bodies was dramatically prolonged in Drd2^M6.36R mice, quinpirole inhibition of dopamine release in the striatum was not altered. This could reflect differences between axonal and somatodendritic compartments or between responses proximal to and distal from the receptor. The results support a pathogenic role for these D2 receptor point mutations in mouse models of human hyperkinetic disorders. SIGNIFICANCE STATEMENT: Two dopamine receptor mutations cause movement disorders. Both are activating mutations; however, D2-M^6.36R is activated more than D2-I212F, paralleling the more severe phenotype of D2-M^6.36R in people. The phenotype of mice with D2-M^6.36R is also more severe. These mice will help develop drug therapy.