Zijun Li1, Xiaoyang Li1, and Bing Yu1
1Shengjing Hospital of China Medical University, Shenyang, China
Synopsis
In the current study we investigated the effect of DRD4 DNA methylation levels on the GABA concentrations in mPFC in PNE children.
Our results suggested the DNA methylation level of DRD4 is associated with increased GABA concentrations in the mPFC in PNE children. The effects of epigenetic variation of the DRD4 DNA on GABA concentrations in mPFC may help us understand the epigenetic susceptibility of the DRD4 DNA methylation to PNE.
INTRODUCTION
Recent studies have shown that
the genotype of dopamine D4 receptor (DRD4) were associated with structural and
functional abnormalities in children suffer from primary nocturnal enuresis
(PNE). However,the effect of
DRD4 DNA methylation
levels on concentrations of gamma amino butyric acid (GABA)in the medial prefrontal cortex (mPFC) is important but remained to unknown. Hence we
carried investigation to explore the effect of DRD4 DNA methylation levels on
the GABA concentrations in mPFC in PNE
children.METHODS
Epigenetic and GABA MRS
data were acquired from 107 PNE patients (9.0–13.9 years, with a median age of 11.5 years) and 104 healthy
controls (9.1–14.0 years, with a median age of 11.3
years) . Methylation levels were assayed for the island of 18 CpG sites in the
DRD4 receptor gene. The DRD4 DNA methylation percentage was calculated for each
subject.
MEGA-PRESS sequence was
applied to measure GABA spectra (TR/TE=2000/68ms, Dynamic scans =320,Spectral BW
(Hz) =2000,total scan time= 10 min 56 sec) using a
3T MRI scanner (Ingenia, Philips Healthcare) while subjects were at rest. The 40×30×24 mm MRS voxel was placed in the mPFC. MRS
data were post-processed using Gannet 3.0 software package (https://github.com/richardedden/Gannet3.0/).
The GABA+ concentrations (CSF-corrected) were calculated.
Comparisons of GABA concentrations
in the mPFC and percentages of DRD4 DNA methylation were performed using the Mann–Whitney U test method between groups. Spearman’s correlation
analysis was performed to explore the relationship between GABA concentrations
in the mPFC and percentages of DRD4 DNA methylation.RESULTS
Percentages of DRD4 DNA methylation of the PNE group were significantly higher than those of the healthy control
group (Z = 4.488, P <0.001). GABA concentrations
of the PNE group were significantly higher than those of the healthy control
group in the mPFC (Z = 9.793, P <0.001). The GABA concentration of mPFC also showed a significant
positively correlation with the percentage of DRD4 DNA methylation within PNE
group (r = 0.791, P < 0.001).DISCUSSION
This research showed the PNE children exhibit increased GABA concentrations in mPFC.
Hypothesis is raised that the DRD4 DNA methylation may lead to down regulation
of DRD4 transcription.
Thus, the DNA methylation-related
decrease in the DRD4 receptor may weaken the inhibition of depolarization
evoked by Calcium-dependent GABA release, causing increased GABA concentrations in
the mPFC.
The mPFC is an important
node of the default mode network and is also the central node in the functional
architecture of the sleep cycle that contains the majority of neurons
controlling the sleep ‘active’ and ‘inactive’ states. Therefore, the increased mPFC
GABA concentration may affect the switching between sleep/waking .
It has also been shown
that the anterior thalamic radiation, which connects the medial prefrontal cortex and
the thalamus, is responsive to bladder filling, so the increased GABA concentration of mPFC may also inhibit the
processing of afferent signals from the bladder to cortex and result in
nocturnal enuresis.CONCLUSION
Our results suggested the DNA methylation level of DRD4 is associated with increased GABA concentrations in the mPFC in PNE children, and more validation tests with more cases and other measurement aspects are needed. The effects of epigenetic variation of the DRD4 DNA on GABA concentrations in mPFCs may help us understand the epigenetic susceptibility of the DRD4 DNA methylation to PNE.Acknowledgements
No acknowledgement found.References
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