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

Elife. 2020 Jun 9;9:e51093. doi: 10.7554/eLife.51093.

Abstract

Early Huntington's disease (HD) include over-activation of dopamine D1 receptors (D1R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1R over-activation, we present a strategy based on targeting complexes of D1R and histamine H3 receptors (H3R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D1R-induced cell death signaling and neuronal degeneration, are mitigated by an H3R antagonist. We demonstrate that the D1R-H3R 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 H3R antagonist prevented cognitive and motor learning deficits and the loss of heteromer expression. Taken together, our results indicate that D1R - H3R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD.

Keywords: dopamine; g-protein coupled receptors; histamine; huntington's disease; mouse; neuroscience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Drug Delivery Systems / methods*
  • Female
  • Gene Knock-In Techniques
  • HEK293 Cells
  • Humans
  • Huntington Disease / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Piperidines / pharmacology
  • Receptors, Dopamine D1* / chemistry
  • Receptors, Dopamine D1* / genetics
  • Receptors, Dopamine D1* / metabolism
  • Receptors, Histamine H3* / chemistry
  • Receptors, Histamine H3* / genetics
  • Receptors, Histamine H3* / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Visual Cortex / cytology

Substances

  • Piperidines
  • Receptors, Dopamine D1
  • Receptors, Histamine H3
  • Recombinant Fusion Proteins
  • thioperamide