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

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Two human dopamine D2 receptor (DRD2) mutations, c.634A>T (p.Ile212Phe, D2-I212F) and c.1121T>G (p.Met374Arg, D2-M^6.36R), are linked to dominant hyperkinetic movement disorders.
• Both mutations are gain-of-function variants affecting G protein-mediated signaling, with D2-M^6.36R exhibiting a greater gain-of-function, correlating with more severe clinical phenotypes.

Purpose of the Study:

• To investigate the functional consequences of the D2-M^6.36R mutation in a mouse model.
• To compare the phenotype of D2-M^6.36R knock-in mice with existing D2-I212F knock-in mice and wild-type controls.

Main Methods:

• Generation and characterization of Drd2^M6.36R knock-in mice.
• Behavioral assessments including gait analysis, locomotor activity, and rotarod performance.
• Electrophysiological recordings of inhibitory postsynaptic conductances in midbrain dopamine neurons.
• Measurement of acetylcholine and dopamine release in neostriatal slices using D2 receptor agonists and antagonists.

Main Results:

• Drd2^M6.36R mice displayed gait abnormalities, a two-fold increase in locomotor activity, and impaired motor coordination in females.
• Prolonged inhibitory postsynaptic conductances were observed in midbrain dopamine neurons of heterozygous Drd2^M6.36R mice compared to D2-I212F and WT mice.
• D2 receptor-mediated inhibition of acetylcholine release was impaired in both knock-in models, but sulpiride reversal was significantly reduced only in Drd2^M6.36R+/- mice.

Conclusions:

• The D2-M^6.36R mutation leads to a more severe phenotype in mice, mirroring the human clinical observations.
• Altered dopamine D2 receptor function, particularly in midbrain dopamine neurons, contributes to the pathogenesis of hyperkinetic movement disorders.
• These mouse models provide valuable tools for developing targeted therapeutic strategies for DRD2-associated movement disorders.