Association of SLC1A2 and SLC17A7 polymorphisms with major depressive disorder in a Thai population

© 2018B. Thaweethee et al., published by Sciendo. Major depressive disorder (MDD) is a common psychiatric disorder with high prevalence and high risk of suicide. Genetic variation of glutamate transporters may associate with MDD and suicide attempt. To evaluate polymorphisms of excitatory amino acid transporter 2 gene (SLC1A2; rs752949, rs1885343, rs4755404, and rs4354668) and vesicular glutamate transporter 1 gene (SLC17A7; rs1043558, rs2946848, and rs11669017) in patients with MDD with and without suicide attempt, and determine the association of these polymorphisms with age of onset and severity of MDD. DNA was extracted from blood taken from patients with MDD (n = 100; including nonsuicidal [n = 50] and suicidal [n = 50] subgroups) and controls (n = 100). Genotyping was conducted using TaqMan single-nucleotide polymorphism (SNP) genotyping. We found a significant difference in SLC17A7 rs2946848 genotype distribution between patients in the MDD and control groups (P = 0.016). Moreover, significant differences in SLC1A2 rs752949 (P = 0.022) and SLC17A7 rs2946848 (P = 0.026) genotype distributions were observed between patients in the nonsuicidal MDD and suicidal MDD groups. SLC1A2 rs1885343 A allele carriers showed significantly lower age of onset than GG genotype (P = 0.049). Furthermore, the severity of MDD indicated by the Hamilton Depression Rating Scale (HDRS) score of G allele carriers of SLC1A2 rs4755404 was significantly greater than the CC genotype (P = 0.013). Polymorphisms of SLC1A2 and SLC17A7 may contribute to the risk of MDD and/or suicide attempt. An association of an SLC1A2 polymorphism with the severity of MDD was apparent

Association study of the functional Catechol-OMethyltranferase (COMT) Val¹⁵⁸Met polymorphism on executive cognitive function in a Thai sample

Catechol-O-Methyltranferase (COMT) plays a crucial role in the removal of cortical dopamine and is strongly implicated in human executive function. Numerous studies have reported associations of the COMT Val158Met (rs4680) polymorphism with executive function in healthy subjects. However, little work has investigated this in the Thai population and the relationship of age and education with this association remains unclear. Therefore, this study was designed to investigate the association of this polymorphism of the COMT gene with executive cognitive brain function in healthy subjects and the relationship with age and education. The Wisconsin Card Sorting Test (WCST) was performed to assess executive function in 254 healthy Thai subjects (aged 20-72 years). The results showed a significant association of rs4680 with executive function, in which Val/Met heterozygotes demonstrated better cognitive set shifting performance. Moreover, Met allele carriers showed a significantly stronger effect in the categories completed score than did Val homozygotes. Furthermore, age and education also showed a significant association with COMT genotype and WCST. These results revealed that executive cognitive function is associated with COMT genotype and influenced by age and/or education level in a Thai sample

Increased DNA methylation in the parvalbumin gene promoter is associated with methamphetamine dependence

Aim: The parvalbumin (PV)-containing subgroup of GABAergic neurons is particularly affected in schizophrenia and animal models of psychosis, including after methamphetamine (METH) administration. We investigated whether METH dependence and METH-induced psychosis may involve an effect on DNA methylation of the PVALB promoter. Materials & methods: The methylation of a PVALB promoter sequence was determined in 100 METH-dependent and 102 control subjects using pyrosequencing. Results: A significant increase in PVALB methylation was observed in METH dependence and METH-induced psychosis. No significant effect on long interspersed nucleotide element-1 methylation, a measure of global DNA methylation, was observed. Conclusion: These results demonstrate a specific association between elevated PVALB methylation and METH-induced psychosis. This finding may contribute to the GABAergic deficits associated with METH dependence

Parvalbumin Promoter Methylation Altered in Major Depressive Disorder

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

Changes of BDNF exon IV DNA methylation are associated with methamphetamine dependence

Aim: We investigated DNA methylation of BDNF in methamphetamine (METH) dependence in humans and an animal model. Materials & methods: BDNF methylation at exon IV was determined by pyrosequencing of blood DNA from METH-dependent and control subjects, and from rat brain following an escalating dose of METH or vehicle. Bdnf expression was determined in rat brain. Results: BDNF methylation was increased in human METH dependence, greatest in subjects with psychosis and in prefrontal cortex of METH-administered rats; rat hippocampus showed reduced Bdnf methylation and increased gene expression. Conclusion: BDNF methylation is abnormal in human METH dependence, especially METH-dependent psychosis, and in METH-administered rats. This may influence BDNF expression and contribute to the neurotoxic effects of METH exposure

Cholinergic-estrogen interaction is associated with the effect of education on attenuating cognitive sex differences in a Thai healthy population

The development of human brain is shaped by both genetic and environmental factors. Sex differences in cognitive function have been found in humans as a result of sexual dimorphism in neural information transmission. Numerous studies have reported the positive effects of education on cognitive functions. However, little work has investigated the effect of education on attenuating cognitive sex differences and the neural mechanisms behind it based on healthy population. In this study, the Wisconsin Card Sorting Test (WCST) was employed to examine sex differences in cognitive function in 135 Thai healthy subjects, and label-free quantitative proteomic method and bioinformatic analysis were used to study sex-specific neurotransmission-related protein expression profiles. The results showed sex differences in two WCST sub-scores: percentage of Total corrects and Total errors in the primary education group (Bayes factor>100) with males performed better, while such differences eliminated in secondary and tertiary education levels. Moreover, 11 differentially expressed proteins (DEPs) between men and women (FDR<0.1) were presented in both education groups, with majority of them upregulated in females. Half of those DEPs interacted directly with nAChR3, whereas the other DEPs were indirectly connected to the cholinergic pathways through interaction with estrogen. These findings provided a preliminary indication that a cholinergic-estrogen interaction relates to, and might underpin, the effect of education on attenuating cognitive sex differences in a Thai healthy population

Proteomic association with age-dependent sex differences in Wisconsin Card Sorting Test performance in healthy Thai subjects

Sex differences in cognitive function exist, but they are not stable and undergo dynamic change during the lifespan. However, our understanding of how sex-related neural information transmission evolves with age is still in its infancy. This study utilized the Wisconsin Card Sorting Test (WCST) and the label-free proteomics method with bioinformatic analysis to investigate the molecular mechanisms underlying age-related sex differences in cognitive performance in 199 healthy Thai subjects (aged 20–70 years), as well as explore the sex-dependent protein complexes for predicting cognitive aging. The results showed that males outperformed females in two of the five WCST sub-scores: %Corrects and %Errors. Sex differences in these scores were related to aging, becoming noticeable in those over 60. At the molecular level, differently expressed individual proteins and protein complexes between both sexes are associated with the potential N-methyl-D-aspartate type glutamate receptor (NMDAR)-mediated excitotoxicity, with the NMDAR complex being enriched exclusively in elderly female samples. These findings provided a preliminary indication that healthy Thai females might be more susceptible to such neurotoxicity, as evidenced by their cognitive performance. NMDAR protein complex enrichment in serum could be proposed as a potential indication for predicting cognitive aging in healthy Thai females

Cytotoxic effects of Saccharomyces cerevisiae TC6 and Lactobacillus brevis TBRC 3003 isolated from Thai fermented foods

Purpose: To determine the cytotoxic effect, anti-colony formation effect and antimigratory effect of Saccharomyces cerevisiae TC6 isolated from Thai water kefir, and Lactobacillus brevis TBRC 3003 isolated from picked cabbage. Methods: Crude microbial extracts were obtained from whole cultures (cells and broths) using ethyl acetate as extracting solvent, and the dried extracts were redissolved in ethanol before use. Cytotoxic, antiproliferative and antimigratory effects of the two microbial extracts on MCF-7, HepG2, and HeLa were tested using 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetra zolium bromide (MTT), clonogenic formation and wound healing assays. Results: Lb. brevis TBRC 3003 showed the highest cytotoxicity toward HepG2 cells (IC50 of 669.72 µg/mL), while S. cerevisiae TC6 showed the highest cytotoxicity against MCF-7 (IC50 of 691.49 µg/mL) and HeLa (IC50 of 379.16 µg/mL) based on MTT assay. Anti-colony formation test showed that S. cerevisiae TC6 was most the most effective in inhibiting colony formation of HepG2 (IC50 of 311.12 µg/mL) and HeLa (IC50 of 494.64 µg/mL), while Lb. brevis TBRC 3003 was the most potent in inhibiting colony formation of MCF-7 (IC50 of 267.88 µg/mL). Conclusion: Both microbes can potentially be implemented in functional foods as bio-therapeutics with chemopreventive properties against breast, liver and cervical cancers

Advancing schizophrenia drug discovery : optimizing rodent models to bridge the translational gap

Although our knowledge of the pathophysiology of schizophrenia has increased, treatments for this devastating illness remain inadequate. Here, we critically assess rodent models and behavioural end points used in schizophrenia drug discovery and discuss why these have not led to improved treatments. We provide a perspective on how new models, based on recent advances in the understanding of the genetics and neural circuitry underlying schizophrenia, can bridge the translational gap and lead to the development of more effective drugs. We conclude that previous serendipitous approaches should be replaced with rational strategies for drug discovery in integrated preclinical and clinical programmes. Validation of drug targets in disease-based models that are integrated with translationally relevant end point assessments will reduce the current attrition rate in schizophrenia drug discovery and ultimately lead to therapies that tackle the disease process