Search

Abstract: There is an increasing evidence that prenatal and early postnatal stressors have life long impacts on physical and mental health problems. Animal studies have shown that this could include enduring changes to brain serotonin neurotransmission. In the present study, we tested whether perinatal adversity in humans has a long-term impact on brain serotonin neurotransmission in adulthood. Twenty-six healthy males, recruited from a 27-year longitudinal study, underwent a positron emission tomography scan with the tracer alpha-[11C]methyl-l-tryptophan (11C-AMT), as an index of serotonin synthesis capacity. The trapping constant is taken as a proxy for the regional 5-HT synthesis. Birth complications, especially a delivery where the fetus showed signs of physiological distress, predicted lower 11C-AMT trapping in the hippocampus and medial orbitofrontal cortex. Lower 11C-AMT trapping in the medial orbitofrontal cortex was also predicted by maternal smoking and lower birth weight. There were no effects of childhood or recent adversity. This is the first human study reporting associations between perinatal adversity and adult 11C-AMT trapping in the hippocampus and medial orbitofrontal cortex. The associations suggest that limbic serotonin pathways may be particularly vulnerable to environmental challenges during the period when they undergo the most prominent neurodevelopmental changes. In combination with other risk factors, perinatal stressors may contribute to increased vulnerability for psychiatric disorders in which serotonin plays a major role. [Copyright &y& Elsevier]

Abstract: Acute tryptophan depletion (ATD) in currently depressed patients has no immediate effect on symptoms, but leads to transient symptom improvement or worsening the next day. In view of recent findings concerning the cognitive effects of serotonin manipulations, we used ATD in fourteen depressed patients to investigate whether cognitive effects following ATD predict symptom changes. We found that symptom improvement 24h after ATD was associated with an improved recall of positive words and with less attentional bias and recall of negative words, 5h after ATD. These results indicate that serotonergic alterations affect emotional processing which may subsequently lead to symptom changes. [Copyright &y& Elsevier]

Early adversity can influence gene expression via epigenetic mechanisms, including DNA methylation. Peripheral tissues are essential in psychiatric epigenetics, as methylation generally cannot be assessed in the living human brain. Several magnetic resonance imaging (MRI) studies show associations of peripheral serotonin transporter gene (SLC6A4) methylation with function and/or structure of frontal-limbic circuits and brain's resting-state. Commonly used samples are derived from blood, saliva or buccal cells. However, little is known regarding which peripheral tissue is most strongly associated with human brain processes. The aim of the current study was to compare the extent of the association between peripheral SLC6A4 promoter methylation and frontal-limbic function, structure and resting-state in healthy individuals across peripheral tissues. Forty healthy prospectively-followed adults underwent anatomical, resting-state and functional MRI. Saliva-, blood- and buccal-derived DNA methylation was assessed by pyrosequencing. Blood-derived SLC6A4 methylation was positively associated with superior frontal gray matter (GM) volume and with right lateral parietal area (RLP)-frontal pole regional resting-state functional connectivity (rsFC). Saliva-derived SLC6A4 methylation was positively associated with superior frontal GM volume. Buccal-derived SLC6A4 methylation was positively associated with superior and inferior frontal and anterior cingulate cortical (ACC) GM volumes, and with RLP-ACC, frontal pole and medial prefrontal regional rsFC. Current results confirmed the relevance of peripheral methylation for frontal-limbic processes in humans. Buccal cells may be the most sensitive cell type when studying SLC6A4 promoter methylation and its associated risk for neural vulnerability and resilience for psychopathologies in which serotonin is implicated. These data should be further validated in clinical populations. [ABSTRACT FROM AUTHOR]

Numerous studies have been using peripheral tissues (e.g., blood or saliva) for DNA methylation analyses in psychiatric epigenetics. The glucocorticoid receptor gene (NR3C1) was among the first ones to show DNA methylation changes due to adverse social environment. Importantly, the NR3C1 gene has several alternative promoters, out of which the 1-F showed increased DNA methylation level at a transcription factor binding site. Afterwards, its co-chaperone molecule, FK506-binding protein 5 (FKBP5) gained interest, showing allele-specific demetylation in its glucocorticoid response element of the 7th intron. This decreased methylation at FKBP5 can lead to NR3C1 resistance, because of an impaired intracellular negative feedback loop. While it is now standard for epigenome-wide DNA methylation analyses to control for cell heterogeneity using cell count estimates derived from the DNA methylation profiles, this important technical variable of cell composition is rarely included in candidate gene analyses. Therefore, we aimed to (1) develop a panel of pyrosequencing assays for cell-specific CG-sites, and (2) evaluate the effect of cell ratio on DNA methylation levels of candidate gene regions in frequently used peripheral tissues, such as Whole Blood (WB), Peripheral Blood Mononuclear Cell (PBMC), as well as non-invasively collected buccal, mouthwash, and saliva samples in two cohorts. Samples were collected from 51 adults participating in a Montreal-based longitudinal cohort, out of which 16 men had been assessed twice. In addition, 38 female patients with borderline personality disorder and 21 control women were recruited at a psychiatric clinic in Budapest. Candidate gene regions of the NR3C1-1F and FKBP5-intron7, as well as tissue-specific CG-sites were assessed by pyrosequencing at both sites. The DNA methylation level of the CG-island in the NR3C1-1F promoter region showed little variance in all of the tissue types we investigated. However, the low CG-density region of FKBP5-intron7 was highly variable across samples, especially in saliva. Notably, methylation level of the epithelial cell marker PTPN7 cg18384097 varied widely among the mouth-related samples in both cohorts (ranging from 9%-95%), even in buccal swab samples, where there was ~ 80% buccal cell ratio on average with 10–12% SD. The effect of epithelial cell composition was substantial on FKBP5-intron7 methylation levels in saliva and mouthwash samples (r=0.5–0.7), but it was less pronounced in buccal swab samples (r=0.2–0.4). Higher ratio of epithelial cells resulted in lower methylation level at the studied FKBP5 CG-sites. Importantly, the stability of the DNA methylation level of this gene region was significant both in saliva and buccal swab samples (r=0.6–0.8, p<0.01). In addition, methylation level of the T lymphocyte marker CD3E cg06164961 also showed correlation with FKBP5-intron7 methylation in blood samples (WB: r=0.5–0.7, PBMC: r=0.3–0.5). Our preliminary results show that cell composition should be taken into account at candidate gene DNA methylation analyses, especially when measuring low CG-density regions in heterogeneous peripheral tissues, such as whole blood or saliva. Using more homogeneous biological samples, e.g., PBMC or purified leukocytes would result in less technical variability. The non-invasively obtained buccal swabs can also yield a relatively homogeneous surrogate sample in psychiatric epigenetics. [ABSTRACT FROM AUTHOR]