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Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus
Dnmt3a2, a de novo DNA methyltransferase, is induced by neuronal activity and participates in long-term memory formation with the increased expression of synaptic plasticity genes. We wanted to determine if Dnmt3a2 with its partner Dnmt3L may influence motor behavior via the dopaminergic system. To...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504350/ https://www.ncbi.nlm.nih.gov/pubmed/32878077 http://dx.doi.org/10.3390/ijms21176297 |
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author | Cui, Di Mesaros, Andrea Burdeos, Gregor Voigt, Ingo Giavalisco, Patrick Hinze, Yvonne Purrio, Martin Neumaier, Bernd Drzezga, Alexander Obata, Yayoi Endepols, Heike Xu, Xiangru |
author_facet | Cui, Di Mesaros, Andrea Burdeos, Gregor Voigt, Ingo Giavalisco, Patrick Hinze, Yvonne Purrio, Martin Neumaier, Bernd Drzezga, Alexander Obata, Yayoi Endepols, Heike Xu, Xiangru |
author_sort | Cui, Di |
collection | PubMed |
description | Dnmt3a2, a de novo DNA methyltransferase, is induced by neuronal activity and participates in long-term memory formation with the increased expression of synaptic plasticity genes. We wanted to determine if Dnmt3a2 with its partner Dnmt3L may influence motor behavior via the dopaminergic system. To this end, we generated a mouse line, Dnmt3a2/3L(Dat)(/wt), with dopamine transporter (DAT) promotor driven Dnmt3a2/3L overexpression. The mice were studied with behavioral paradigms (e.g., cylinder test, open field, and treadmill), brain slice patch clamp recordings, ex vivo metabolite analysis, and in vivo positron emission tomography (PET) using the dopaminergic tracer 6-[(18)F]FMT. The results showed that spontaneous activity and exercise performance were enhanced in Dnmt3a2/3L(Dat)(/wt) mice compared to Dnmt3a2/3L(wt)(/wt) controls. Dopaminergic substantia nigra pars compacta neurons of Dnmt3a2/3L(Dat)(/wt) animals displayed a higher fire frequency and excitability. However, dopamine concentration was not increased in the striatum, and dopamine metabolite concentration was even significantly decreased. Striatal 6-[(18)F]FMT uptake, reflecting aromatic L-amino acid decarboxylase activity, was the same in Dnmt3a2/3L(Dat)(/wt) mice and controls. [(18)F]FDG PET showed that hypothalamic metabolic activity was tightly linked to motor behavior in Dnmt3a2/3L(Dat)(/wt) mice. Furthermore, dopamine biosynthesis and motor-related metabolic activity were correlated in the hypothalamus. Our findings suggest that Dnmt3a2/3L, when overexpressed in dopaminergic neurons, modulates motor performance via activation of the nigrostriatal pathway. This does not involve increased dopamine synthesis. |
format | Online Article Text |
id | pubmed-7504350 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75043502020-09-24 Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus Cui, Di Mesaros, Andrea Burdeos, Gregor Voigt, Ingo Giavalisco, Patrick Hinze, Yvonne Purrio, Martin Neumaier, Bernd Drzezga, Alexander Obata, Yayoi Endepols, Heike Xu, Xiangru Int J Mol Sci Article Dnmt3a2, a de novo DNA methyltransferase, is induced by neuronal activity and participates in long-term memory formation with the increased expression of synaptic plasticity genes. We wanted to determine if Dnmt3a2 with its partner Dnmt3L may influence motor behavior via the dopaminergic system. To this end, we generated a mouse line, Dnmt3a2/3L(Dat)(/wt), with dopamine transporter (DAT) promotor driven Dnmt3a2/3L overexpression. The mice were studied with behavioral paradigms (e.g., cylinder test, open field, and treadmill), brain slice patch clamp recordings, ex vivo metabolite analysis, and in vivo positron emission tomography (PET) using the dopaminergic tracer 6-[(18)F]FMT. The results showed that spontaneous activity and exercise performance were enhanced in Dnmt3a2/3L(Dat)(/wt) mice compared to Dnmt3a2/3L(wt)(/wt) controls. Dopaminergic substantia nigra pars compacta neurons of Dnmt3a2/3L(Dat)(/wt) animals displayed a higher fire frequency and excitability. However, dopamine concentration was not increased in the striatum, and dopamine metabolite concentration was even significantly decreased. Striatal 6-[(18)F]FMT uptake, reflecting aromatic L-amino acid decarboxylase activity, was the same in Dnmt3a2/3L(Dat)(/wt) mice and controls. [(18)F]FDG PET showed that hypothalamic metabolic activity was tightly linked to motor behavior in Dnmt3a2/3L(Dat)(/wt) mice. Furthermore, dopamine biosynthesis and motor-related metabolic activity were correlated in the hypothalamus. Our findings suggest that Dnmt3a2/3L, when overexpressed in dopaminergic neurons, modulates motor performance via activation of the nigrostriatal pathway. This does not involve increased dopamine synthesis. MDPI 2020-08-31 /pmc/articles/PMC7504350/ /pubmed/32878077 http://dx.doi.org/10.3390/ijms21176297 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Cui, Di Mesaros, Andrea Burdeos, Gregor Voigt, Ingo Giavalisco, Patrick Hinze, Yvonne Purrio, Martin Neumaier, Bernd Drzezga, Alexander Obata, Yayoi Endepols, Heike Xu, Xiangru Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus |
title | Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus |
title_full | Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus |
title_fullStr | Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus |
title_full_unstemmed | Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus |
title_short | Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus |
title_sort | dnmt3a2/dnmt3l overexpression in the dopaminergic system of mice increases exercise behavior through signaling changes in the hypothalamus |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504350/ https://www.ncbi.nlm.nih.gov/pubmed/32878077 http://dx.doi.org/10.3390/ijms21176297 |
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