Modulation of dopamine D1 receptors via histamine H3 receptors is a novel therapeutic target for Huntington's disease

Moreno-Delgado, David, Puigdellívol, Mar, Moreno, Estefanía, Rodríguez-Ruiz, Mar, Botta, Joaquín, Gasperini, Paola, Chiarlone, Anna, Howell, Lesley A., Scarselli, Marco, Casadó, Vicent, Cortés, Antoni, Ferré, Sergi, Guzmán, Manuel, Lluís, Carmen, Alberch, Jordi, Canela, Enric I., Ginés, Silvia and McCormick, Peter J. (2020) Modulation of dopamine D1 receptors via histamine H3 receptors is a novel therapeutic target for Huntington's disease. eLife, 9. pp. 1-31. ISSN 2050-084X

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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.

Item Type: Article
Uncontrolled Keywords: dopamine,g-protein coupled receptors,histamine,huntington's disease,mouse,neuroscience,neuroscience(all),immunology and microbiology(all),biochemistry, genetics and molecular biology(all) ,/dk/atira/pure/subjectarea/asjc/2800
Faculty \ School: Faculty of Science > School of Pharmacy
Related URLs:
Depositing User: LivePure Connector
Date Deposited: 19 Jun 2020 23:56
Last Modified: 27 Sep 2020 23:59
URI: https://ueaeprints.uea.ac.uk/id/eprint/75722
DOI: 10.7554/eLife.51093

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