TY  - JOUR
AU  - Cui, Di
AU  - Mesaros, Andrea
AU  - Burdeos, Gregor
AU  - Voigt, Ingo
AU  - Giavalisco, Patrick
AU  - Hinze, Yvonne
AU  - Purrio, Martin
AU  - Neumaier, Bernd
AU  - Drzezga, Alexander
AU  - Obata, Yayoi
AU  - Endepols, Heike
AU  - Xu, Xiangru
TI  - Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus
JO  - International journal of molecular sciences
VL  - 21
IS  - 17
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - FZJ-2021-02689
SP  - 6297 -
PY  - 2020
AB  - 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, Dnmt3a2/3LDat/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-[18F]FMT. The results showed that spontaneous activity and exercise performance were enhanced in Dnmt3a2/3LDat/wt mice compared to Dnmt3a2/3Lwt/wt controls. Dopaminergic substantia nigra pars compacta neurons of Dnmt3a2/3LDat/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-[18F]FMT uptake, reflecting aromatic L-amino acid decarboxylase activity, was the same in Dnmt3a2/3LDat/wt mice and controls. [18F]FDG PET showed that hypothalamic metabolic activity was tightly linked to motor behavior in Dnmt3a2/3LDat/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.
LB  - PUB:(DE-HGF)16
C6  - 32878077
UR  - <Go to ISI:>//WOS:000569576000001
DO  - DOI:10.3390/ijms21176297
UR  - https://juser.fz-juelich.de/record/893315
ER  -