Modulation of dopamine D(1) receptors via histamine H(3) receptors is a novel therapeutic target for Huntington's disease

Early Huntington’s disease (HD) include over-activation of dopamine D(1) receptors (D(1)R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D(1)R over-activation, we present a strategy based on targeting complexes of D(1)R and histamine H(3) receptors (H(3)R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D(1)R-induced cell death signaling and neuronal degeneration, are mitigated by an H(3)R antagonist. We demonstrate that the D(1)R-H(3)R heteromer is expressed in HD mice at early but not late stages of HD, correlating with HD progression. In accordance, we found this target expressed in human control subjects and low-grade HD patients. Finally, treatment of HD mice with an H(3)R antagonist prevented cognitive and motor learning deficits and the loss of heteromer expression. Taken together, our results indicate that D(1)R - H(3)R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD.