Modulation of dopamine D1 receptors via histamine H3 receptors is a novel therapeutic target for Huntington's disease
- University of Barcelona, Spain
- William Harvey Research Institute, Queen Mary University of London, United Kingdom
- University of Trento, Italy
- Instituto Ramon y Cajal de Investigacion Sanitaria, Universidad Complutense, Spain
- Queen Mary University of London, United Kingdom
- University of Pisa, Italy
- National Institutes of Health, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
BBSRC CASE (MCCORMICK_U15BB)
- Peter J McCormick
RSC Grant Project (RG140118)
- Peter J McCormick
BBSRC (BB/N504282/3)
- Peter J McCormick
Ministerio de Economia y Competitividad (RTI2018-094374-B-I00)
- Silvia Ginés
Fundació la Marató de TV3 (20140610)
- Enric I Canela
Jerome LeJeune Foundation (FJL-01/01/2013)
- Peter J McCormick
Ministerio de Economia y Competitividad (SAF2017-88076-R)
- Jordi Alberch
Ministerio de Economia y Competitividad (RTI2018-095311-B-I00)
- Manuel Guzmán
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures involving animals were performed in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and approved by the local animal care committee of the Universitat de Barcelona (99/01) and Generalitat de Catalunya (99/1094), in accordance with the European (2010/63/EU) and Spanish (RD53/2013) regulations for the care and use of laboratory animals. All protocols involving postmortem human sample were approved by the institutional ethic committees.
Copyright
© 2020, Moreno-Delgado et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Modulation of dopamine D1 receptors via histamine H3 receptors is a novel therapeutic target for Huntington's disease
eLife 9:e51093.
https://doi.org/10.7554/eLife.51093
