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
-
- 3,360
- views
-
- 328
- downloads
-
- 29
- 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
Avoiding distraction by salient yet irrelevant stimuli is critical when accomplishing daily tasks. One possible mechanism to accomplish this is by suppressing stimuli that may be distracting such that they no longer compete for attention. While the behavioral benefits of distractor suppression are well established, its neural underpinnings are not yet fully understood. In a functional MRI (fMRI) study, we examined whether and how sensory responses in early visual areas show signs of distractor suppression after incidental learning of spatial statistical regularities. Participants were exposed to an additional singleton task where, unbeknownst to them, one location more frequently contained a salient distractor. We analyzed whether visual responses in terms of fMRI BOLD were modulated by this distractor predictability. Our findings indicate that implicit spatial priors shape sensory processing even at the earliest stages of cortical visual processing, evident in early visual cortex as a suppression of stimuli at locations which frequently contained distracting information. Notably, while this suppression was spatially (receptive field) specific, it did extend to nearby neutral locations and occurred regardless of whether distractors, nontarget items, or targets were presented at this location, suggesting that suppression arises before stimulus identification. Crucially, we observed similar spatially specific neural suppression even if search was only anticipated, but no search display was presented. Our results highlight proactive modulations in early visual cortex, where potential distractions are suppressed preemptively, before stimulus onset, based on learned expectations. Combined, our study underscores how the brain leverages implicitly learned prior knowledge to optimize sensory processing and attention allocation.
-
- Neuroscience
To navigate real-world listening conditions, the auditory system relies on the integration of multiple sources of information. However, to avoid inappropriate cross-talk between inputs, highly connected neural systems need to strike a balance between integration and segregation. Here, we develop a novel approach to examine how repeated neurochemical modules in the mouse inferior colliculus lateral cortex (LC) allow controlled integration of its multimodal inputs. The LC had been impossible to study via imaging because it is buried in a sulcus. Therefore, we coupled two-photon microscopy with the use of a microprism to reveal the first-ever sagittal views of the LC to examine neuronal responses with respect to its neurochemical motifs under anesthetized and awake conditions. This approach revealed marked differences in the acoustic response properties of LC and neighboring non-lemniscal portions of the inferior colliculus. In addition, we observed that the module and matrix cellular motifs of the LC displayed distinct somatosensory and auditory responses. Specifically, neurons in modules demonstrated primarily offset responses to acoustic stimuli with enhancement in responses to bimodal stimuli, whereas matrix neurons showed onset response to acoustic stimuli and suppressed responses to bimodal stimulation. Thus, this new approach revealed that the repeated structural motifs of the LC permit functional integration of multimodal inputs while retaining distinct response properties.
