Modulation of dopamine D1 receptors via histamine H3 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 striatal cell model and HD 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 animal models 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, as well as 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. Impact Statement Progression of Huntington’s disease can be slowed by altering dopamine signalling through the Dopamine 1 receptor - Histamine 3 receptor heteromer.