Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Cui, Di, Mesaros, Andrea, Burdeos, Gregor, Voigt, Ingo, Giavalisco, Patrick, Hinze, Yvonne, Purrio, Martin, Neumaier, Bernd, Drzezga, Alexander, Obata, Yayoi, Endepols, Heike, Xu, Xiangru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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
_version_ 1783584604396978176
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
work_keys_str_mv AT cuidi dnmt3a2dnmt3loverexpressioninthedopaminergicsystemofmiceincreasesexercisebehaviorthroughsignalingchangesinthehypothalamus
AT mesarosandrea dnmt3a2dnmt3loverexpressioninthedopaminergicsystemofmiceincreasesexercisebehaviorthroughsignalingchangesinthehypothalamus
AT burdeosgregor dnmt3a2dnmt3loverexpressioninthedopaminergicsystemofmiceincreasesexercisebehaviorthroughsignalingchangesinthehypothalamus
AT voigtingo dnmt3a2dnmt3loverexpressioninthedopaminergicsystemofmiceincreasesexercisebehaviorthroughsignalingchangesinthehypothalamus
AT giavaliscopatrick dnmt3a2dnmt3loverexpressioninthedopaminergicsystemofmiceincreasesexercisebehaviorthroughsignalingchangesinthehypothalamus
AT hinzeyvonne dnmt3a2dnmt3loverexpressioninthedopaminergicsystemofmiceincreasesexercisebehaviorthroughsignalingchangesinthehypothalamus
AT purriomartin dnmt3a2dnmt3loverexpressioninthedopaminergicsystemofmiceincreasesexercisebehaviorthroughsignalingchangesinthehypothalamus
AT neumaierbernd dnmt3a2dnmt3loverexpressioninthedopaminergicsystemofmiceincreasesexercisebehaviorthroughsignalingchangesinthehypothalamus
AT drzezgaalexander dnmt3a2dnmt3loverexpressioninthedopaminergicsystemofmiceincreasesexercisebehaviorthroughsignalingchangesinthehypothalamus
AT obatayayoi dnmt3a2dnmt3loverexpressioninthedopaminergicsystemofmiceincreasesexercisebehaviorthroughsignalingchangesinthehypothalamus
AT endepolsheike dnmt3a2dnmt3loverexpressioninthedopaminergicsystemofmiceincreasesexercisebehaviorthroughsignalingchangesinthehypothalamus
AT xuxiangru dnmt3a2dnmt3loverexpressioninthedopaminergicsystemofmiceincreasesexercisebehaviorthroughsignalingchangesinthehypothalamus