Parvalbumin Promoter Methylation Altered in Major Depressive Disorder

Abstract

Aims: To determine the extent of DNA methylation of parvalbumin gene (PVALB) promoter in major depressive disorder (MDD) patients with and without suicide attempt in comparison with healthy controls.Methods: The extracted DNA from dried blood spots of MDD patients (n = 92) including non-suicidal MDD and suicidal-MDD subgroups (n = 45 and n = 47, respectively) and age-matched control subjects (n = 95) was used for DNA methylation analysis at four CpG sites in the promoter sequence of PVALB by pyrosequencing.Results: The PVALB methylation was significantly increased at CpG2 and decreased at CpG4 in the MDD group compared to the control group, while there was no difference between non-suicidal MDD and suicidal-MDD subgroups. A significant inverse correlation of severity of MDD was indicated only for CpG4.Conclusion: This study provides the first evidence of abnormalities of PVALB promoter methylation in MDD and its correlation with MDD severity indicating a role for epigenetics in this psychiatric disorder.

Early life adversity drives sex-dependent changes in 5-mC DNA methylation of parvalbumin cells in the prefrontal cortex in rats

“…CpG site 40 showed higher methylation levels (>15%), though there were no significant effects observed from our manipulations on methylation percentage at this site. These findings are inconsistent with past findings of hypermethylation of CpG site 40 for both MDD patients (Thaweethee-Sukjai et al, 2019) and schizophrenia rodent models (Fachim et al, 2016). However, the fact that there was a lot of variability in samples and many samples that showed no methylation, this may obscure subtle effects.…”

“…Patients with schizophrenia show reduced PFC density of PV-containing interneurons (Kaar et al, 2019). Additionally, in humans with schizophrenia or major depressive disorder, and in mouse models of schizophrenia, hypermethylation of the Pvalb promoter is associated with decreased PV protein (Fachim et al, 2018; Thaweethee-Sukjai et al, 2019). Changes in PV protein output in response to methylation suggest that the Pvalb promoter region is sensitive to methylation, and that methylation impacts the transcriptional profile of PV.…”

Sex Differences in Affective Dysfunction and Alterations in Parvalbumin in Rodent Models of Early Life Adversity

“…One widely observed neural change involves alterations in overall inhibitory/GABAergic function (Page and Coutellier, 2019 ; Prévot and Sibille, 2021 ), which are likely exacerbated by adverse experiences (Maguire, 2014 ). Parvalbumin (PV), a calcium-binding protein expressed within a specific subset of GABAergic neurons, is thought to be involved in affective dysregulation characteristic of anxiety (e.g., Page et al, 2019 ; Xiao et al, 2020 ) and depression (e.g., Perova et al, 2015 ; Thaweethee-Sukjai et al, 2019 ). Indeed, reduced PV levels are associated with increased anxiety-like behavior and affective dysfunction in rodent studies (Godavarthi et al, 2014 ; Lussier and Stevens, 2016 ; Xu et al, 2016 ; Todorović et al, 2019 ; Vojtechova et al, 2021 ) and indirectly in human studies looking at Tourette syndrome, which is thought to be closely related to anxiety (Kalanithi et al, 2005 ; Kataoka et al, 2009 ).…”

Integrated Analysis of Methylomic and Transcriptomic Data to Identify Potential Diagnostic Biomarkers for Major Depressive Disorder

“…In a prospective analysis of major depressive disorder in adolescent girls, the authors found that all four significant CpGs in NR3C1 were in the gene body region: Two sites were located within a transcription factor-binding site (TFBS) region, one was in a region of open chromatin, and one site associated with an enhancer element [ 47 ]. Benjamard et al [ 48 ] reported that in the promoter region of parvalbumin, methylation was significantly increased at CpG2 and decreased at CpG4 in the MDD group compared to the control group. Some alterations of CpGs are limited to specific gene phenotypes.…”