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.
Article and author information
Author details
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.
Metrics
-
- 3,299
- views
-
- 322
- downloads
-
- 27
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Neuroscience
The circadian clock, an internal time-keeping system orchestrates 24 hr rhythms in physiology and behavior by regulating rhythmic transcription in cells. Astrocytes, the most abundant glial cells, play crucial roles in CNS functions, but the impact of the circadian clock on astrocyte functions remains largely unexplored. In this study, we identified 412 circadian rhythmic transcripts in cultured mouse cortical astrocytes through RNA sequencing. Gene Ontology analysis indicated that genes involved in Ca2+ homeostasis are under circadian control. Notably, Herpud1 (Herp) exhibited robust circadian rhythmicity at both mRNA and protein levels, a rhythm disrupted in astrocytes lacking the circadian transcription factor, BMAL1. HERP regulated endoplasmic reticulum (ER) Ca2+ release by modulating the degradation of inositol 1,4,5-trisphosphate receptors (ITPRs). ATP-stimulated ER Ca2+ release varied with the circadian phase, being more pronounced at subjective night phase, likely due to the rhythmic expression of ITPR2. Correspondingly, ATP-stimulated cytosolic Ca2+ increases were heightened at the subjective night phase. This rhythmic ER Ca2+ response led to circadian phase-dependent variations in the phosphorylation of Connexin 43 (Ser368) and gap junctional communication. Given the role of gap junction channel (GJC) in propagating Ca2+ signals, we suggest that this circadian regulation of ER Ca2+ responses could affect astrocytic modulation of synaptic activity according to the time of day. Overall, our study enhances the understanding of how the circadian clock influences astrocyte function in the CNS, shedding light on their potential role in daily variations of brain activity and health.
-
- Neuroscience
The relation between neural activity and behaviorally relevant variables is at the heart of neuroscience research. When strong, this relation is termed a neural representation. There is increasing evidence, however, for partial dissociations between activity in an area and relevant external variables. While many explanations have been proposed, a theoretical framework for the relationship between external and internal variables is lacking. Here, we utilize recurrent neural networks (RNNs) to explore the question of when and how neural dynamics and the network’s output are related from a geometrical point of view. We find that training RNNs can lead to two dynamical regimes: dynamics can either be aligned with the directions that generate output variables, or oblique to them. We show that the choice of readout weight magnitude before training can serve as a control knob between the regimes, similar to recent findings in feedforward networks. These regimes are functionally distinct. Oblique networks are more heterogeneous and suppress noise in their output directions. They are furthermore more robust to perturbations along the output directions. Crucially, the oblique regime is specific to recurrent (but not feedforward) networks, arising from dynamical stability considerations. Finally, we show that tendencies toward the aligned or the oblique regime can be dissociated in neural recordings. Altogether, our results open a new perspective for interpreting neural activity by relating network dynamics and their output.
