Abstract
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.
Highlights
Accumulative studies have demonstrated epigenetic factors as a potent regulator for brain function in the nervous system
In order to generate dopaminergic neuron-specific Dnmt3a2/3L overexpression mouse cohorts (Dnmt3a2/3LDat/wt), the cre/loxp system (Supplementary Figure S1) was used to cross flox-Dnmt3a2/3L females [20] with Dat-cre males [21], and the offspring were further characterized by DAB
The expression of Dnmt3a2 of Dnmt3a2/3LDat/wt was increased in the olfactory bulb (OB), striatum (ST) and mid brain (MB) where the DA neurons located, but not in other parts of the brain, e.g., frontal cortex (FC) (Figure 1C)
Summary
Accumulative studies have demonstrated epigenetic factors as a potent regulator for brain function in the nervous system. DNA methylation as one of the major epigenetic processes is mediated by DNA methyltransferases These enzymes regulate many important cellular processes involved in neuronal activity and brain functions [4,5,6], such as neuron survival, differentiation, memory formation, and several neuropsychological impairments. We wanted to determine whether Dnmt3a2 with its cofactor Dnmt3L (Dnmt3a2/3L) influences DA activity To this end, a dopaminergic neuron-specific Dnmt3a2/3L overexpression transgenic mouse line (Dnmt3a2/3LDat/wt) was generated. The dopaminergic neurons of the substantia nigra pars compacta (SNc) have been intensively studied and their electrophysiological properties are well known [17] Their firing characteristics are homogeneous, even subtle deviations from the common pattern can be detected. We studied the mice with a combination of brain slice electrophysiology, behavioral experiments, in vivo positron emission tomography (PET), indirect calorimetry, and post-mortem metabolite extraction
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