Cargando…
Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism
The dopamine (DA) system has a profound impact on reward-motivated behavior and is critically involved in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although DA defects are found in autistic patients, it is not well defined how the DA pathways are altered in ASD and whethe...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418402/ https://www.ncbi.nlm.nih.gov/pubmed/32778145 http://dx.doi.org/10.1186/s13041-020-00649-7 |
_version_ | 1783569683059834880 |
---|---|
author | Chao, Owen Y. Pathak, Salil S. Zhang, Hao Dunaway, Nathan Li, Jay-Shake Mattern, Claudia Nikolaus, Susanne Huston, Joseph P. Yang, Yi-Mei |
author_facet | Chao, Owen Y. Pathak, Salil S. Zhang, Hao Dunaway, Nathan Li, Jay-Shake Mattern, Claudia Nikolaus, Susanne Huston, Joseph P. Yang, Yi-Mei |
author_sort | Chao, Owen Y. |
collection | PubMed |
description | The dopamine (DA) system has a profound impact on reward-motivated behavior and is critically involved in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although DA defects are found in autistic patients, it is not well defined how the DA pathways are altered in ASD and whether DA can be utilized as a potential therapeutic agent for ASD. To this end, we employed a phenotypic and a genetic ASD model, i.e., Black and Tan BRachyury T(+)Itpr3(tf)/J (BTBR) mice and Fragile X Mental Retardation 1 knockout (Fmr1-KO) mice, respectively. Immunostaining of tyrosine hydroxylase (TH) to mark dopaminergic neurons revealed an overall reduction in the TH expression in the substantia nigra, ventral tegmental area and dorsal striatum of BTBR mice, as compared to C57BL/6 J wild-type ones. In contrast, Fmr1-KO animals did not show such an alteration but displayed abnormal morphology of TH-positive axons in the striatum with higher “complexity” and lower “texture”. Both strains exhibited decreased expression of striatal dopamine transporter (DAT) and increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1, a label for glutamatergic terminals) and TH signals, while GABAergic neurons quantified by glutamic acid decarboxylase 67 (GAD67) remained intact. Intranasal administration of DA rescued the deficits in non-selective attention, object-based attention and social approaching of BTBR mice, likely by enhancing the level of TH in the striatum. Application of intranasal DA to Fmr1-KO animals alleviated their impairment of social novelty, in association with reduced striatal TH protein. These results suggest that although the DA system is modified differently in the two ASD models, intranasal treatment with DA effectively rectifies their behavioral phenotypes, which may present a promising therapy for diverse types of ASD. |
format | Online Article Text |
id | pubmed-7418402 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-74184022020-08-12 Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism Chao, Owen Y. Pathak, Salil S. Zhang, Hao Dunaway, Nathan Li, Jay-Shake Mattern, Claudia Nikolaus, Susanne Huston, Joseph P. Yang, Yi-Mei Mol Brain Research The dopamine (DA) system has a profound impact on reward-motivated behavior and is critically involved in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although DA defects are found in autistic patients, it is not well defined how the DA pathways are altered in ASD and whether DA can be utilized as a potential therapeutic agent for ASD. To this end, we employed a phenotypic and a genetic ASD model, i.e., Black and Tan BRachyury T(+)Itpr3(tf)/J (BTBR) mice and Fragile X Mental Retardation 1 knockout (Fmr1-KO) mice, respectively. Immunostaining of tyrosine hydroxylase (TH) to mark dopaminergic neurons revealed an overall reduction in the TH expression in the substantia nigra, ventral tegmental area and dorsal striatum of BTBR mice, as compared to C57BL/6 J wild-type ones. In contrast, Fmr1-KO animals did not show such an alteration but displayed abnormal morphology of TH-positive axons in the striatum with higher “complexity” and lower “texture”. Both strains exhibited decreased expression of striatal dopamine transporter (DAT) and increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1, a label for glutamatergic terminals) and TH signals, while GABAergic neurons quantified by glutamic acid decarboxylase 67 (GAD67) remained intact. Intranasal administration of DA rescued the deficits in non-selective attention, object-based attention and social approaching of BTBR mice, likely by enhancing the level of TH in the striatum. Application of intranasal DA to Fmr1-KO animals alleviated their impairment of social novelty, in association with reduced striatal TH protein. These results suggest that although the DA system is modified differently in the two ASD models, intranasal treatment with DA effectively rectifies their behavioral phenotypes, which may present a promising therapy for diverse types of ASD. BioMed Central 2020-08-10 /pmc/articles/PMC7418402/ /pubmed/32778145 http://dx.doi.org/10.1186/s13041-020-00649-7 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Chao, Owen Y. Pathak, Salil S. Zhang, Hao Dunaway, Nathan Li, Jay-Shake Mattern, Claudia Nikolaus, Susanne Huston, Joseph P. Yang, Yi-Mei Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism |
title | Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism |
title_full | Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism |
title_fullStr | Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism |
title_full_unstemmed | Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism |
title_short | Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism |
title_sort | altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418402/ https://www.ncbi.nlm.nih.gov/pubmed/32778145 http://dx.doi.org/10.1186/s13041-020-00649-7 |
work_keys_str_mv | AT chaooweny altereddopaminergicpathwaysandtherapeuticeffectsofintranasaldopamineintwodistinctmousemodelsofautism AT pathaksalils altereddopaminergicpathwaysandtherapeuticeffectsofintranasaldopamineintwodistinctmousemodelsofautism AT zhanghao altereddopaminergicpathwaysandtherapeuticeffectsofintranasaldopamineintwodistinctmousemodelsofautism AT dunawaynathan altereddopaminergicpathwaysandtherapeuticeffectsofintranasaldopamineintwodistinctmousemodelsofautism AT lijayshake altereddopaminergicpathwaysandtherapeuticeffectsofintranasaldopamineintwodistinctmousemodelsofautism AT matternclaudia altereddopaminergicpathwaysandtherapeuticeffectsofintranasaldopamineintwodistinctmousemodelsofautism AT nikolaussusanne altereddopaminergicpathwaysandtherapeuticeffectsofintranasaldopamineintwodistinctmousemodelsofautism AT hustonjosephp altereddopaminergicpathwaysandtherapeuticeffectsofintranasaldopamineintwodistinctmousemodelsofautism AT yangyimei altereddopaminergicpathwaysandtherapeuticeffectsofintranasaldopamineintwodistinctmousemodelsofautism |