Serotonin Transporter Gene Research Articles

Effect of STIN2VNTR polymorphism of the serotonin transporter gene on background EEG in aged subjects depends on the intellectual environment of professional activity

Previously, we found that associations between the STin2VNTR polymorphism of the serotonin transporter gene and cognitive characteristics during aging depend on the intellectual environment of professional activity. In this regard, the present study was aimed to investigate the age-related characteristics of the electrical activity of the brain depending on this polymorphism and long-term intellectual training. We examined EEG power indicators in subjects of the younger (YG, 18–35 years, N = 261) and older (OG, 55–80 years, N = 142) age groups. According to the intellectual richness of the professional activity environment, the subjects were divided into scientists (SA) and those engaged in non-scientific activities (NSA). All subjects were genotyped for the STin2VNTR polymorphism of the serotonin transporter gene. It was found that the power of delta-beta1 rhythms in older carriers of the 10/10 and 12/12 genotypes was opposite in SA and NSA groups (in the SA group 10/10 12/12, in the NSA 12/12 10/10) while similar effects in young subjects were absent. In the absence of cognitive training, genetic differences were determined by an age-related decrease in the power of delta-alpha3 rhythms in carriers of the 10/10 genotype with no age-related differences in carriers of the 12/12 genotype, suggesting the resistance of the 12/12 genotype to age-related changes. In contrast, under cognitive training conditions, there were no age differences in the 10/10 genotype, and a decrease in power was observed in the 12/12 genotype, suggesting an effect of cognitive training on both homozygous genotypes. The decrease in power observed for the 10/10 NSA and 12/12 SA genotypes appears to have different physiological significance, since it was accompanied by changes in attentional efficiency only in the NSA group. The work shows for the first time that the background EEG features associated with the STin2VNTR polymorphism of the serotonin transporter gene in elderly people are under the modulating influence of long-term cognitive training, determined by the specificity of professional activity.

Unraveling the Serotonergic Mechanism of Stress-Related Anxiety: Focus on Co-Treatment with Resveratrol and Selective Serotonin Reuptake Inhibitors

Background/Objectives: In post-traumatic stress disorder (PTSD), anxiety-like symptoms are often associated with elevated noradrenaline levels and decreased serotonin. Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat anxiety, but elevated serotonin has been observed in some anxiety disorders. This study investigates stress-induced anxiety as an immediate effect of chronic stress exposure using the predator stress paradigm. Methods: We examined serotonin levels, serotonin transporter (SERT), and 5-HT3A receptor gene expression in response to stress. The effects of SSRIs (paroxetine, sertraline) and resveratrol on these parameters were also analyzed, alongside co-treatment with resveratrol and sertraline. Results: Chronic stress exposure led to a significant increase in serotonin levels and upregulation of SERT and 5-HT3A receptor expression. SSRIs failed to prevent anxiety or reduce serotonin levels, partly due to suppressed SERT expression. Resveratrol downregulated SERT and 5-HT3A expression less than SSRIs but effectively reduced anxiety and restored serotonin, likely by upregulating MAO-A expression. Co-treatment with resveratrol and sertraline produced the strongest anxiolytic effect. Conclusions: Elevated serotonin and increased expression of SERT and 5-HT3A receptor genes are key factors in stress-related anxiety. Resveratrol and SSRIs target these mechanisms, suggesting potential therapeutic strategies for anxiety disorders. Future research will focus on further elucidating the serotonergic mechanisms involved and identifying new anxiolytic drug targets.

Interaction of Val66Met Brain-Derived Neurotrophic Factor and 5-HTTLPR Serotonin Transporter Gene Polymorphisms with Lifetime Prevalence of Post-Traumatic Stress Disorder in Primary Care Patients

Background/Objectives: Post-traumatic stress disorder (PTSD) is a complex condition influenced by both genetic and environmental factors. This longitudinal study aimed to explore the connection between two specific genetic polymorphisms, Val66Met and 5-HTTLPR, and the lifetime prevalence of PTSD in patients from primary care settings. We also examined the role of sociodemographic and psychosocial factors to provide a more comprehensive view of PTSD risk. Methods: We recruited a cohort of primary care patients and diagnosed PTSD using a standardized diagnostic interview. Genetic analyses focused on Val66Met and 5-HTTLPR polymorphisms. We applied logistic regression to assess the association between these genetic markers and PTSD, considering factors such as gender, family history of depression, and experiences of childhood maltreatment. Results: Our findings show that women, individuals with a family history of depression, and those exposed to childhood maltreatment have a higher risk of developing PTSD. While the Val66Met polymorphism was not significantly associated with PTSD, the 5-HTTLPR polymorphism showed a marginal relationship. No significant interaction was found between the two polymorphisms in relation to PTSD. Conclusions: This study underscores the multifactorial nature of PTSD, influenced by both genetic and environmental factors. The findings point to the importance of further research on genetic predispositions and highlight the value of early interventions for high-risk populations in primary care settings.

8429 Serotonin Receptor Antagonist Alleviates Vascular Defects Produced by Selective Serotonin Reuptake Inhibitor Treatment During Gestation

Abstract Disclosure: L.P. Agnew: None. R. Domingues: None. A. Weichmann: None. L.L. Hernandez: None. Maternal mental health is critical for both mother and infant and often antidepressant therapy outweighs the potential risks of selective serotonin reuptake inhibitor (SSRI) treatment; however, SSRI use is associated with adverse neonatal outcomes. Preliminary work in our laboratory revealed placental apoptosis in pregnant dams treated with fluoxetine (FLX) and dams genetically deficient for the serotonin transporter gene. We hypothesize that SSRIs decrease placental blood flow, causing apoptosis and organ death via signaling through the serotonin 2A/2C receptors. Pregnant female C57BL6 mice were randomized to be treated daily, via I.P. injection, from E10-17.5 with saline (CON; n=6), 2 mg/kg FLX (n=5), or 2 mg/kg ketanserin plus 2 mg/kg FLX (n=5). On E17.5, using high-resolution ultrasound imaging, we identified the uterine artery, individual umbilical cords, and placental disc blood vessels. We calculated blood pressure, blood volume, blood flow rate, and heart rate in the uterine artery, umbilical cord, and placental disc. FLX (decreased blood volume in the uterine artery compared to ketanserin plus FLX (48.42 ± 18.26, 116.54 ± 45.25; p=0.0077), and decreased average (89.38 ± 31.50) and peak (130.36 ± 39.05) blood velocity in the uterine artery compared to ketanserin plus FLX average (162.76 ± 68.46; p=0.0322) and peak (236.77 ± 92.43; p=0.0242) blood velocity. FLX decreased average (0.04 + 0.02) and peak (0.07 ± 0.04) blood pressure in the uterine artery compared to ketanserin and FLX treated animals average (0.12 ± 0.10; p=0.0634) and peak (0.25 ± 0.19; p=0.0412) blood pressure. Ketanserin plus FLX (391 ± 38.29) decreased heart rate (BPM) in the placental disc compared to untreated controls (450.67 ± 26.08; p=0.0128). In the umbilical cord, ketanserin plus FLX (393 ± 28.25) decreased BPM compared to CON (450.17 ± 29.44; p=0.0078) and compared to FLX treatment alone (437.20 ± 17.28; p=0.0450). FLX treatment of dams during pregnancy reduces blood flow volume, heart rate, and blood flow velocity to the placenta via the uterine artery. The use of ketanserin, an inhibitor of serotonin receptor 2A/2C signaling, in combination with FLX, reduced the effects of FLX on the uterine artery. These data suggest that treatment with ketanserin could be utilized to alleviate the reproductive side effects of antidepressant usage for pregnant mothers while allowing the mother to remain on antidepressants. Future research should further investigate the effects of SSRI and ketanserin on blood flow to the fetus through the umbilical cord. Presentation: 6/2/2024

8429 Serotonin Receptor Antagonist Alleviates Vascular Defects Produced by Selective Serotonin Reuptake Inhibitor Treatment During Gestation

Abstract Disclosure: L.P. Agnew: None. R. Domingues: None. A. Weichmann: None. L.L. Hernandez: None. Maternal mental health is critical for both mother and infant and often antidepressant therapy outweighs the potential risks of selective serotonin reuptake inhibitor (SSRI) treatment; however, SSRI use is associated with adverse neonatal outcomes. Preliminary work in our laboratory revealed placental apoptosis in pregnant dams treated with fluoxetine (FLX) and dams genetically deficient for the serotonin transporter gene. We hypothesize that SSRIs decrease placental blood flow, causing apoptosis and organ death via signaling through the serotonin 2A/2C receptors. Pregnant female C57BL6 mice were randomized to be treated daily, via I.P. injection, from E10-17.5 with saline (CON; n=6), 2 mg/kg FLX (n=5), or 2 mg/kg ketanserin plus 2 mg/kg FLX (n=5). On E17.5, using high-resolution ultrasound imaging, we identified the uterine artery, individual umbilical cords, and placental disc blood vessels. We calculated blood pressure, blood volume, blood flow rate, and heart rate in the uterine artery, umbilical cord, and placental disc. FLX (decreased blood volume in the uterine artery compared to ketanserin plus FLX (48.42 ± 18.26, 116.54 ± 45.25; p=0.0077), and decreased average (89.38 ± 31.50) and peak (130.36 ± 39.05) blood velocity in the uterine artery compared to ketanserin plus FLX average (162.76 ± 68.46; p=0.0322) and peak (236.77 ± 92.43; p=0.0242) blood velocity. FLX decreased average (0.04 + 0.02) and peak (0.07 ± 0.04) blood pressure in the uterine artery compared to ketanserin and FLX treated animals average (0.12 ± 0.10; p=0.0634) and peak (0.25 ± 0.19; p=0.0412) blood pressure. Ketanserin plus FLX (391 ± 38.29) decreased heart rate (BPM) in the placental disc compared to untreated controls (450.67 ± 26.08; p=0.0128). In the umbilical cord, ketanserin plus FLX (393 ± 28.25) decreased BPM compared to CON (450.17 ± 29.44; p=0.0078) and compared to FLX treatment alone (437.20 ± 17.28; p=0.0450). FLX treatment of dams during pregnancy reduces blood flow volume, heart rate, and blood flow velocity to the placenta via the uterine artery. The use of ketanserin, an inhibitor of serotonin receptor 2A/2C signaling, in combination with FLX, reduced the effects of FLX on the uterine artery. These data suggest that treatment with ketanserin could be utilized to alleviate the reproductive side effects of antidepressant usage for pregnant mothers while allowing the mother to remain on antidepressants. Future research should further investigate the effects of SSRI and ketanserin on blood flow to the fetus through the umbilical cord. Presentation: 6/2/2024

The Association of Genetic Polymorphisms and Atypical Depression in Adults: A Systematic Review.

Atypical depression (AD) is a clinical subtype of depression characterised by mood reactivity and at least two of the following features: significant weight gain/increased appetite, hypersomnia, leaden paralysis, and/or interpersonal rejection sensitivity. The role of genetics in the development of depression remains a considerable level of interest among individuals. Due to the large number of breakthrough studies in genetics, there is currently a wealth of heterogeneous data on the existence of genetic markers for depression, including AD. However, it appears that there is a gap in the literature, as we were unable to identify any systematic reviews or meta-analyses that comprehensively describe these data. Therefore, our research aims to provide high-quality, solid evidence for further studies in this area. Electronic bibliographic databases (Scopus, MEDLINE) were systematically searched from inception to September 2023. We searched for any specific genetic markers that could be retrieved associated with AD. The quality of studies has been assessed by means of the Q-genie tool. Nine studies meeting the inclusion criteria were selected, which appeared to link genetic polymorphisms to atypical depression. Four studies examined genetic polymorphisms associated with the serotonin transporter gene (5-HTT), three studies examined genetic polymorphisms associated with endocrine regulation, two studies considered genetic polymorphisms associated with immune and/or cellular regulation, specifically the melanin-concentrating hormone receptor 2 (MCHR2), mineralocorticoid receptor (MR), and fat mass and obesity-associated protein (FTO) genes involved in the regulation of energy balance. The extracted data confirm that the atypical type of major depressive disorder is heritable to a certain extent. Individual risk markers for developing this type of depression may be identified in the future.

Development of a method for the imputation of the multi-allelic serotonin-transporter-linked polymorphic region (5-HTTLPR) in the Japanese population.

Serotonin-transporter-linked polymorphic region (5-HTTLPR), a variable number of tandem repeats in the promoter region of serotonin transporter gene, is classified into short (S) and long (L) alleles. Initial case-control association studies claiming the risks of the S allele in depression and anxiety were not completely supported by recent studies. However, most studies, especially those on East Asian populations, have overlooked the complexity of 5-HTTLPR, which involves multiple different alleles with distinct functional properties. To address this issue, distinguishing multiple 5-HTTLPR alleles is essential. Here, using the 5-HTTLPR genotypes previously determined by exhaustive Sanger sequencing of approximately 1,500 Japanese subjects and their comprehensive SNP data, we constructed a method for 5-HTTLPR genotype imputation. We identified 28 tag SNPs for the imputation of four major 5-HTTLPR alleles, which collectively account for 97.6% of 5-HTTLPR alleles in the Japanese population. Our imputation method, achieved an accuracy of 0.872 in cross-validation, will contribute to association analysis of 5-HTTLPR in the Japanese subjects.

Dopamine and Serotonin Transporter Genes Regulation in Highly Sensitive Individuals during Stressful Conditions: A Focus on Genetics and Epigenetics.

Background: Coping with stress is essential for mental well-being and can be critical for highly sensitive individuals, characterized by a deeper perception and processing of stimuli. So far, the molecular bases characterizing high-sensitivity traits have not been completely investigated and gene × environment interactions might play a key role in making some people more susceptible than others. Methods: In this study, 104 young adult university students, subjects that might face overwhelming experiences more than others, were evaluated for the genetics and epigenetics of dopamine (DAT1) and serotonin (SERT) transporter genes, in addition to the expression of miR-132, miR-491, miR-16, and miR-135. Results: We found an increase in DNA methylation at one specific CpG site at DAT1 5'UTR in highly sensitive students reporting high levels of perceived stress when compared to those less sensitive and/or less stressed. Moreover, considering DAT1 VNTR at 3'UTR, we observed that this effect was even more pronounced in university students having the 9/9 genotype when compared to those with the 9/10 genotype. These data are corroborated by the higher levels of miR-491, targeting DAT1, in highly sensitive subjects with high levels of perceived stress. SERT gene DNA methylation at one specific CpG site was reported to instead be higher in subjects reporting lower perceived stress when compared to more stressed subjects. Consistently, miR-135 expression, regulating SERT, was lower in subjects with higher perceived stress. Conclusions: We here suggest that the correlation of DAT1 and SERT genetic and epigenetic data with the analysis of stress and sensitivity might be useful to suggest possible biomarkers to monitor mental health wellness in vulnerable subjects.

Fibromyalgia progression and association with other diseases and inheritance with management practices in humans

Fibromyalgia is a widespread pain disorder characterized by chronic, diffuse pain, about 1 to 5% around world. While more prevalent in women and adults, it can also manifest in children and adolescents. The specific pathophysiology of fibromyalgia remains unclear, but it is associated with neuronal over sensitization, reduced conditioned pain modulation, cognitive dysfunction, memory loss, and impaired information processing. It has now been categorized as a somatic symptom disorder. This study aimed to investigate fibromyalgia, focusing on its potential hereditary connections and management practices. A key pathophysiological aspect of fibromyalgia is central sensitization, marked by increased functional connectivity with pre-receptive brain areas, decreased connectivity with antinociceptive areas, and alterations in central nervous system neurotransmitters, also in size and shape of specific brain areas. Fibromyalgia is not directly inherited from parents to offspring, it does exhibit a tendency to cluster within families. The serotonin transporter gene, characterized by single nucleotide polymorphism with "S" (short) allele, is more prevalent in individuals with fibromyalgia and psychological distress. In conclusion, fibromyalgia is a widespread pain disorder with a substantial impact on the central nervous system, resulting in significant disability and an elevated risk of chronic diseases. Early diagnosis and intervention can minimize the impact of fibromyalgia. Physical therapy and non-drug therapies should be customized for each patient. The FDA has approved three drugs including pregabalin, duloxetine, and milnacipran for fibromyalgia treatment.

Early-life adversity severity, timing, and context type are associated with SLC6A4 methylation in emerging adults: Results from a prospective cohort study

BackgroundEpigenetic modifications, including DNA methylation (DNAm), can play a role in the biological embedding of early-life adversity (ELA) through serotonergic mechanisms. The current study examines methylation of the CpG island in the promoter region of the stress-responsive serotonin transporter gene (SLC6A4) and is the first to jointly assess how it is influenced by ELA severity, timing, and type—specifically, deprivation and threat. MethodsWe use data from 627 Youth Emotion Project study participants, recruited from two US high schools. Using adjusted linear regressions, we analyze DNA collected in early adulthood from 410 participants and ELA based on interviewer-rated responses from concurrent Childhood Trauma Interviews, adjusting for survey-measured covariates. ResultsELA robustly predicted mean CpG island SLC6A4 DNAm percent across 71 CpG sites. Each additional major-severity ELA event was associated with a 0.121-percentage-point increase (p<0.001), equating to a 0.177 standard deviation (sd) higher DNAm level (95 % CI: 0.080, 0.274) with each 1-sd higher adversity score. When modeled separately, both childhood and adolescent ELA predicted SLC6A4 DNAm. When modeled jointly, adolescent ELA was most strongly predictive, and child adversity remained significantly associated with DNAm through indirect associations via adolescent adversity. Additionally, the ELA-SLC6A4 DNAm association may vary by adversity type. Across separate models for childhood and adolescent exposures, deprivation coefficients are positive and statistically significant. Meanwhile, threat coefficients are positive and not significantly significant but do not statistically differ from deprivation coefficients. In models including all ELA dimensions, one major adolescent deprivation event is associated with a 0.222-percentage-point increased SLC6A4 DNAm (p<0.05), or a 1-sd higher deprivation score with a 0.157-sd increased DNAm. ConclusionResults further implicate epigenetic modification on serotonergic neurotransmission via DNAm in the downstream sequelae of ELA—particularly adolescent deprivation—and support preventive interventions in adolescence to mitigate biological embedding.

Association between serotonin transporter gene polymorphism and obsessive–compulsive disorder in the Egyptian population

BackgroundObsessive–compulsive disorder (OCD) is a debilitating disorder that has multifactorial etiology including genetic, neurobiological, cognitive, and environmental influences. Genetic studies have focused on the genes of the serotonin system. This study aimed to look for the possible relation between the polymorphism in the promotor region of the serotonin transporter gene and obsessive–compulsive disorder in the Egyptian population.ResultsThis study included 94 OCD patients and 116 healthy control individuals. Blood samples were collected from all participants for DNA extraction and genotyping. The assessment of patients was done by application of the structured clinical interview according to DSM-V, the dimensional Yale-Brown Obsessive–Compulsive Scale. There was an association between serotonin transporter gene polymorphism and OCD development. The carriage of the short allele was a risk factor for having OCD.ConclusionObsessive–compulsive disorder is associated with serotonin transporter gene polymorphism. This will contribute to considering the genetic information of patients for the prediction of best drug response and tolerability by personalizing the choice of treatment.

The minor allele of the serotonin transporter gene variant rs4251417 is associated with increased resilience in soldiers experiencing acute stress during survival training: preliminary findings

ABSTRACT Background Variation in cognitive, emotional and physical performance in response to stress is attributable to environmental and genetic factors. Ability to adapt to stress is resilience. Objectives This study investigated genetic factors associated with resilience in soldiers exposed to severe stress due to intense physical and mental demands at Survive, Evade, Resist and Escape school, a unique environment to study acute stress and resiliency in real-world circumstances. Design A preliminary correlational study was conducted to identify genetic markers for resilience to stress. Methods Mood state, resiliency and dissociative state of 73 soldiers were assessed using: Connor-Davidson Resilience Scale (CD-RISC); Profile of Mood States (POMS); and Clinician-Administered Dissociative States Scale (CADSS). Change scores for resilience-related stress markers were computed; 116 single nucleotide polymorphisms (SNPs) associated with stress, depression, anxiety, sleep, or psychiatric disorders were assessed. Results A significant association between change in CD-RISC score and SNP rs4251417, present in an intron of SLC6A4, the serotonin transporter gene, was observed. Conclusions Individuals with the minor allele of SNP rs4251417 had a greater positive change in CD-RISC, indicating increased self-assessed resilience. This study suggests the minor allele of SNP rs4251417 of SLC6A4 is associated with resilience when individuals are exposed to high stress.

Morphometric analysis and functional insights into the serotonergic system of Girardia tigrina (Tricladida, Platyhelminthes).

Using immunocytochemistry, serotonergic nerve elements were documented in the nervous system of the planarian Girardia tigrina. Serotonin-immunopositive components were observed in the brain, ventral, dorsal and longitudinal nerve cords, transverse nerve commissures connecting the nerve cords, and in the nerve plexus. Whole-mount preparations of G. tigrina were analyzed by fluorescent and confocal laser scanning microscopy. An essential quantitative morphometric measurement of serotonin-immunopositive structures was conducted in three body regions (anterior, middle, and posterior) of the planarian. The number of serotonin neurons was maximal in the head region. The ventral nerve cords gradually decreased in thickness from anterior to posterior body ends. Physiological action of exogenously applied serotonin was studied in G. tigrina for the first time. It was found that serotonin (0.1 and 1 µmol L-1) accelerated eye regeneration. The transcriptome sequencing performed for the first time for the planarian G. tigrina revealed the transcripts of the tryptophan hydroxylase (trph), amino acid decarboxylase (aadc) and serotonin transporter (sert) genes. The data obtained indicate the presence of the components of serotonin pathway in G. tigrina. The identified transcripts can take part in serotonin turnover and participate in the realization of biological effects of serotonin in planarians, associated with eyes regeneration and differentiation.

Developmental cascades from early childhood attachment security to adolescent level of personality functioning among high-risk youth.

This study examines associations between early childhood attachment security and adolescent personality functioning in a high-risk sample within a developmental psychopathology framework. Data from 2,268 children (1165 male; 1103 female) and caregivers participating in Future of Families and Child Well-Being Study (FFCWS) were used to examine (1) effects of genetic polymorphisms of the serotonin transporter (5-HTTLPR) and dopamine D4 receptor (DRD4) genes and adverse childhood experiences (ACEs) on attachment security and emotional and behavioral dysregulation in early childhood and (2) longitudinal associations and transactional relationships among attachment security, dysregulation, negative parenting attitudes and behaviors, social competence, and adolescent personality functioning. Results revealed that ACEs predicted attachment security over and above sex or the genetic risk, and gene × environment interactions did not increment prediction. Results of cascade models showed that greater early childhood attachment security predicted higher adolescent level of personality functioning via pathways through intermediary variables. Limitations and future research directions are discussed.

From parents to children: associations of traffic risks with impulsivity, family relationships and serotonin transporter genotype.

Road traffic injuries are the leading cause of death for young adults, and parents play a major role in shaping their traffic behaviour. Higher impulsivity (predictor of higher traffic risk) has been shown to be dependent on family relations and the serotonin transporter gene promoter polymorphism (5-HTTLPR). The specific mechanisms for the inheritance of risky traffic behaviour from parents to children are not clear, and the genetic aspect has not been studied before. We used data of Estonian Children Personality Behaviour and Health Study subjects (n = 596, mean age = 25.2 ± 0.6) and their parents (mothers, n = 460, mean age = 52.1 ± 5.8; fathers, n = 339, mean age = 54.1 ± 6.5). Family relationships scale, traffic risk questionnaires and Adaptive and Maladaptive Impulsivity Scale were filled out. The increased risk-taking behaviour of parents and worse quality of family relationship were significant predictors of higher traffic risk among subjects. Family support and impulsivity of fathers significantly predicted the subjects' traffic risk score in interaction with 5-HTTLPR genotype: l'/l' homozygous subjects with adaptively impulsive fathers had higher traffic risk, whereas for s'-allele carrying subjects family support was more significant. Parental role modelling and family relationships are significant predictors of future traffic behaviour of the child. Whether the behavioural example of the father or the influence of family relationships is more important in predicting future risky traffic behaviour, depends on the 5-HTTLPR genotype of the child.

Long-term Environmental Enrichment Normalizes Schizophrenia-like Abnormalities and Promotes Hippocampal Slc6a4 Promoter Demethylation in Mice Submitted to a Two-hit Model

Here, we explored the impact of prolonged environmental enrichment (EE) on behavioral, neurochemical, and epigenetic changes in the serotonin transporter gene in mice subjected to a two-hit schizophrenia model. The methodology involved administering the viral mimetic PolyI:C to neonatal Swiss mice as a first hit during postnatal days (PND) 5–7, or a sterile saline solution as a control. At PND21, mice were randomly assigned either to standard environment (SE) or EE housing conditions. Between PND35-44, the PolyI:C-treated group was submitted to various unpredictable stressors, constituting the second hit. Behavioral assessments were conducted on PND70, immediately after the final EE exposure. Following the completion of behavioral assessments, we evaluated the expression of proteins in the hippocampus that are indicative of microglial activation, such as Iba-1, as well as related to neurogenesis, including doublecortin (Dcx). We also performed methylation analysis on the serotonin transporter gene (Slc6a4) to investigate alterations in serotonin signaling. The findings revealed that EE for 50 days mitigated sensorimotor gating deficits and working memory impairments in two-hit mice and enhanced their locomotor and exploratory behaviors. EE also normalized the overexpression of hippocampal Iba-1 and increased the expression of hippocampal Dcx. Additionally, we observed hippocampal demethylation of the Slc6a4 gene in the EE-exposed two-hit group, indicating epigenetic reprogramming. These results contribute to the growing body of evidence supporting the protective effects of long-term EE in counteracting behavioral disruptions caused by the two-hit schizophrenia model, pointing to enhanced neurogenesis, diminished microglial activation, and epigenetic modifications of serotonergic pathways as underlying mechanisms.

Association of Polymorphisms of the Serotonin Transporter Gene SLC6A4 with Depression

Association of Polymorphisms of the Serotonin Transporter Gene SLC6A4 with Depression

Interactions Between Serotonin Transporter Gene and Adverse Childhood Experience in a Generalized Additive Model: A Pilot Study.

While most people experience potentially traumatic events (PTEs), including Adverse Childhood Experiences (ACEs), the stress reactions to PTEs on mental health outcomes are highly heterogeneous. Resilience is influenced by a complex biopsychosocial ecological system, including gene serotonin transporter-linked promoter region or 5-HTTLPR /rs25531 by ACEs interactions. This pilot study investigated the gene-by-environment interactions on mental health outcomes in adults enrolled in a health care profession program using a generalized additive model (GAM). Seventy health care college students (mean age = 27.4 years, 67.1% women) participated in this cross-sectional study. Saliva samples were collected from students to analyze 5-HTTLPR/rs25531. Participants completed the ACE Questionnaire and the Mental Health Inventory. GAMs with different interaction terms were built adjusting for age, gender, and race. The value of the effective degree of freedom (EDF) quantifies the curvature of the relationship. Among participants with the long allele of 5-HTTLPR/rs25531, a linear pattern was found between the total ACE score and mental health outcomes (EDF = 1). Conversely, among participants with the short allele, EDF was approximately 2, indicating a curved association suggesting that mental health worsens in individuals exposed to up to four types of ACEs. The impact of up to four ACEs on mental health was stronger among individuals with the short allele of 5-HTTLPR/rs25531 than those with the long allele. Although this study does not claim to provide a definite approach to analyzing gene-by-environment interactions, we offer a different perspective to explore the relationship.

Postpartum Depression: Etiology, Treatment, and Consequences for Maternal Care.

Postpartum depression (PPD) is a disabling condition that has recently shown an increase in prevalence, becoming an essential public health problem. This study is a qualitative review summarizing the most frequent risk factors associated with PPD, evaluating molecular aspects of PPD and current approaches to detect and prevent PPD. The most prevalent risk factors were detected in the areas of economic and social factors, obstetrical history, lifestyle, and history of mental illness. Research on the genetic basis for PPD has taken place in recent years to identify the genes responsible for establishing targeted therapeutic methods and understanding its pathogenesis. The most frequently studied candidate gene was the serotonin transporter gene (SERT) associated with PPD. Among biological studies, antidepressants and psychological interventions provided the most evidence of successful intervention. The obstetrician can serve an essential role in screening for and treating PPD. Postpartum women with risk factors should be screened using the Edinburgh Postnatal Depression Scale (EPDS), but, at the moment, there are no prevention programs in Europe. In conclusion, data from this review increase concerns among this vulnerable population and can be used to design a screening tool for high-risk pregnant women and create a prevention program.

Phosphoproteomics implicates glutamatergic and dopaminergic signalling in the antidepressant-like properties of the iron chelator deferiprone

BackgroundCurrent antidepressants have limitations due to insufficient efficacy and delay before improvement in symptoms. Polymorphisms of the serotonin transporter (5-HTT) gene have been linked to depression (when combined with stressful life events) and altered response to selective serotonergic reuptake inhibitors. We have previously revealed the antidepressant-like properties of the iron chelator deferiprone in the 5-HTT knock-out (KO) mouse model of depression. Furthermore, deferiprone was found to alter neural activity in the prefrontal cortex of both wild-type (WT) and 5-HTT KO mice. MethodsIn the current study, we examined the molecular effects of acute deferiprone treatment in the prefrontal cortex of both genotypes via phosphoproteomics analysis. ResultsIn WT mice treated with deferiprone, there were 22 differentially expressed phosphosites, with gene ontology analysis implicating cytoskeletal proteins. In 5-HTT KO mice treated with deferiprone, we found 33 differentially expressed phosphosites. Gene ontology analyses revealed phosphoproteins that were predominantly involved in synaptic and glutamatergic signalling. In a drug-naïve cohort (without deferiprone administration), the analysis revealed 21 differentially expressed phosphosites in 5-HTT KO compared to WT mice. We confirmed the deferiprone-induced increase in tyrosine hydroxylase serine 40 residue phosphorylation (pTH-Ser40) (initially revealed in our phosphoproteomics study) by Western blot analysis, with deferiprone increasing pTH-Ser40 expression in WT and 5-HTT KO mice. ConclusionAs glutamatergic and synaptic signalling are dysfunctional in 5-HTT KO mice (and are the target of fast-acting antidepressant drugs such as ketamine), these molecular effects may underpin deferiprone's antidepressant-like properties. Furthermore, dopaminergic signalling may also be involved in deferiprone's antidepressant-like properties.