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Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders

Tic disorders affect ~5% of the population and are frequently comorbid with obsessive-compulsive disorder, autism, and attention deficit disorder. Histamine dysregulation has been identified as a rare genetic cause of tic disorders; mice with a knockout of the histidine decarboxylase (Hdc) gene repr...

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Autores principales: Rapanelli, M, Frick, L, Pogorelov, V, Ohtsu, H, Bito, H, Pittenger, C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545743/
https://www.ncbi.nlm.nih.gov/pubmed/28117842
http://dx.doi.org/10.1038/tp.2016.290
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author Rapanelli, M
Frick, L
Pogorelov, V
Ohtsu, H
Bito, H
Pittenger, C
author_facet Rapanelli, M
Frick, L
Pogorelov, V
Ohtsu, H
Bito, H
Pittenger, C
author_sort Rapanelli, M
collection PubMed
description Tic disorders affect ~5% of the population and are frequently comorbid with obsessive-compulsive disorder, autism, and attention deficit disorder. Histamine dysregulation has been identified as a rare genetic cause of tic disorders; mice with a knockout of the histidine decarboxylase (Hdc) gene represent a promising pathophysiologically grounded model. How alterations in the histamine system lead to tics and other neuropsychiatric pathology, however, remains unclear. We found elevated expression of the histamine H3 receptor in the striatum of Hdc knockout mice. The H3 receptor has significant basal activity even in the absence of ligand and thus may modulate striatal function in this knockout model. We probed H3R function using specific agonists. The H3 agonists R-aminomethylhistamine (RAMH) and immepip produced behavioral stereotypies in KO mice, but not in controls. H3 agonist treatment elevated intra-striatal dopamine in KO mice, but not in controls. This was associated with elevations in phosphorylation of rpS6, a sensitive marker of neural activity, in the dorsal striatum. We used a novel chemogenetic strategy to demonstrate that this dorsal striatal activity is necessary and sufficient for the development of stereotypy: when RAMH-activated cells in the dorsal striatum were chemogenetically activated (in the absence of RAMH), stereotypy was recapitulated in KO animals, and when they were silenced the ability of RAMH to produce stereotypy was blocked. These results identify the H3 receptor in the dorsal striatum as a contributor to repetitive behavioral pathology.
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spelling pubmed-55457432017-08-07 Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders Rapanelli, M Frick, L Pogorelov, V Ohtsu, H Bito, H Pittenger, C Transl Psychiatry Original Article Tic disorders affect ~5% of the population and are frequently comorbid with obsessive-compulsive disorder, autism, and attention deficit disorder. Histamine dysregulation has been identified as a rare genetic cause of tic disorders; mice with a knockout of the histidine decarboxylase (Hdc) gene represent a promising pathophysiologically grounded model. How alterations in the histamine system lead to tics and other neuropsychiatric pathology, however, remains unclear. We found elevated expression of the histamine H3 receptor in the striatum of Hdc knockout mice. The H3 receptor has significant basal activity even in the absence of ligand and thus may modulate striatal function in this knockout model. We probed H3R function using specific agonists. The H3 agonists R-aminomethylhistamine (RAMH) and immepip produced behavioral stereotypies in KO mice, but not in controls. H3 agonist treatment elevated intra-striatal dopamine in KO mice, but not in controls. This was associated with elevations in phosphorylation of rpS6, a sensitive marker of neural activity, in the dorsal striatum. We used a novel chemogenetic strategy to demonstrate that this dorsal striatal activity is necessary and sufficient for the development of stereotypy: when RAMH-activated cells in the dorsal striatum were chemogenetically activated (in the absence of RAMH), stereotypy was recapitulated in KO animals, and when they were silenced the ability of RAMH to produce stereotypy was blocked. These results identify the H3 receptor in the dorsal striatum as a contributor to repetitive behavioral pathology. Nature Publishing Group 2017-01 2017-01-24 /pmc/articles/PMC5545743/ /pubmed/28117842 http://dx.doi.org/10.1038/tp.2016.290 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Rapanelli, M
Frick, L
Pogorelov, V
Ohtsu, H
Bito, H
Pittenger, C
Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders
title Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders
title_full Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders
title_fullStr Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders
title_full_unstemmed Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders
title_short Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders
title_sort histamine h3r receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545743/
https://www.ncbi.nlm.nih.gov/pubmed/28117842
http://dx.doi.org/10.1038/tp.2016.290
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