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

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Moreno-Delgado, David and Puigdellívol, Mar and Moreno, Moreno and Rodríguez-Ruiz, Mar and Botta, Joaquín and Gasperini, Paola and Chiarlone, Anna and Howell, Lesley A. and Scarselli, Marco and Casadó, Vicent and Cortés, Antoni and Ferré, Sergi and Guzmán, Manuel and Lluís, Carmen and Alberch, Jordi and Canela, Enric I. and 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 (e51093). pp. 1-31. ISSN ESSN 2050-084X

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Official URL: https://elifesciences.org/articles/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.


Item Type:Article
Uncontrolled Keywords:Dopamine; Histamine; Huntington’s disease
Subjects:Medical sciences > Biology > Biochemistry
Medical sciences > Biology > Neurosciences
ID Code:62454
Deposited On:08 Oct 2020 10:13
Last Modified:22 Oct 2020 07:56

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