scholarly journals Neurogenic Plasticity in a Serotonin Transporter Knockout Model: Effects of Maternal and Offspring Genotype

2021 ◽  
Author(s):  
◽  
Sarah Tapnikar
Keyword(s):  
Serotonin Transporter ◽  
Stress Responses ◽  
Neural Plasticity ◽  
Depressive Symptomology ◽  
Genotype Effect ◽  
Maternal Genotype ◽  
Antidepressant Effects ◽  
Maternal Caregiving ◽  
Brdu Immunohistochemistry ◽  
Offspring Genotype

<p>Major depressive disorder (MDD) is debilitating mental disorder that is increasing in prevalence. Many theories have tried to explain the aetiology of depression including the classic monoamine deficiency hypothesis and the newer neurogenic hypothesis. The finding that selective serotonin transporter inhibitors (SSRIs) work by increasing extracellular serotonin levels in the brain and have antidepressant effects has formed the basis of the most widely accepted theory of depression, the monoamine hypothesis. However, a genetic reduction in human and animal serotonin reuptake transporters, which also increases extracellular serotonin, is associated with depressive symptomology. This paradox is not explained by the monoamine hypothesis. The key difference between these two scenarios is that genetically induced increases in serotonin occur from development onward, while SSRIs increase serotonin only in adulthood. Furthermore, SSRIs typically take several weeks to confer a therapeutic effect. This finding has led to the hypothesis that, rather than acute monoamine-increasing effects, it is the downstream effects of such increases on neurogenesis and neural plasticity which confer antidepressant effects. To further elucidate the neurobiology of depression, this study sought to examine the effects of genetically increasing serotonin on early postnatal neurogenesis in a serotonin knockout rat model using BrdU immunohistochemistry. We examined both the offspring and maternal genotype effects. We found that SERT-/- offspring had the highest levels of neurogenesis compared with SERT+/- and SERT+/+ at postnatal day 7. In addition we found a maternal genotype effect with SERT+/+ offspring born and reared by SERT+/- mothers having lower neurogenesis compared to SERT+/+ offspring from SERT+/+ mothers. The potential effects of maternal caregiving, neuroplasticity in altered mood and stress responses and the role of 5-HT receptors are discussed.</p>

scholarly journals Neurogenic Plasticity in a Serotonin Transporter Knockout Model: Effects of Maternal and Offspring Genotype

2021 ◽  
Author(s):  
◽  
Sarah Tapnikar
Keyword(s):  
Serotonin Transporter ◽  
Stress Responses ◽  
Neural Plasticity ◽  
Depressive Symptomology ◽  
Genotype Effect ◽  
Maternal Genotype ◽  
Antidepressant Effects ◽  
Maternal Caregiving ◽  
Brdu Immunohistochemistry ◽  
Offspring Genotype

<p>Major depressive disorder (MDD) is debilitating mental disorder that is increasing in prevalence. Many theories have tried to explain the aetiology of depression including the classic monoamine deficiency hypothesis and the newer neurogenic hypothesis. The finding that selective serotonin transporter inhibitors (SSRIs) work by increasing extracellular serotonin levels in the brain and have antidepressant effects has formed the basis of the most widely accepted theory of depression, the monoamine hypothesis. However, a genetic reduction in human and animal serotonin reuptake transporters, which also increases extracellular serotonin, is associated with depressive symptomology. This paradox is not explained by the monoamine hypothesis. The key difference between these two scenarios is that genetically induced increases in serotonin occur from development onward, while SSRIs increase serotonin only in adulthood. Furthermore, SSRIs typically take several weeks to confer a therapeutic effect. This finding has led to the hypothesis that, rather than acute monoamine-increasing effects, it is the downstream effects of such increases on neurogenesis and neural plasticity which confer antidepressant effects. To further elucidate the neurobiology of depression, this study sought to examine the effects of genetically increasing serotonin on early postnatal neurogenesis in a serotonin knockout rat model using BrdU immunohistochemistry. We examined both the offspring and maternal genotype effects. We found that SERT-/- offspring had the highest levels of neurogenesis compared with SERT+/- and SERT+/+ at postnatal day 7. In addition we found a maternal genotype effect with SERT+/+ offspring born and reared by SERT+/- mothers having lower neurogenesis compared to SERT+/+ offspring from SERT+/+ mothers. The potential effects of maternal caregiving, neuroplasticity in altered mood and stress responses and the role of 5-HT receptors are discussed.</p>

scholarly journals Epigenome-wide associations between observed maternal sensitivity and offspring DNA methylation: a population-based prospective study in children

2020 ◽  
pp. 1-11
Author(s):  
Lorenza Dall’ Aglio ◽  
Jolien Rijlaarsdam ◽  
Rosa H. Mulder ◽  
Alexander Neumann ◽  
Janine F. Felix ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stress Responses ◽  
Association Studies ◽  
Maternal Sensitivity ◽  
Population Based ◽  
Epigenetic Mechanism ◽  
Developmental Problems ◽  
Maternal Caregiving ◽  
Typical Variation

Abstract Background Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment. Methods Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses. Results Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 × 10−07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4. Conclusions These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.

Maternal care and environmental enrichment influences on serotonin knockout mice with implications for a gene x stress model of autism

2019 ◽  
Author(s):  
◽  
Briana M. Kille
Keyword(s):  
Serotonin Transporter ◽  
Maternal Care ◽  
Environmental Enrichment ◽  
Environmental Influence ◽  
Repetitive Behavior ◽  
Critical Time ◽  
University Of Missouri ◽  
Time Period ◽  
Maternal Genotype ◽  
The University

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Previous research has shown a genetic variant in the serotonin transporter gene (Slc6a4) can increase the severity of a person's reaction to stress. This variant interacts with environmental stressors resulting in poorer health outcomes. Previous studies have also found that stressing pregnant mothers who carry the variant can result in an increased likelihood of autism diagnosis for the child. This maternal genotype x prenatal stress interaction has been modeled in the serotonin transporter knockout (SERT KO) mouse--dams genetically modified to mimic humans carrying the short allele were stressed during pregnancy resulting in offspring showing altered social behavior, repetitive behavior, and anxiety behavior. The first study included in this dissertation attempted to replicate this model while using a foster dam paradigm to avoid potential maternal care confounds. Surprisingly, the results showed that equalizing maternal care equalized several group differences in behavior. It is theorized that this is due to elimination of the neonatal insult from poor maternal care that would correspond to a human prenatal insult during a previously identified critical time period. The second study explored the potential effects environmentally enriched home cages on anxiety like behaviors of SERT KO mice. The study showed that all animals, regardless of genotype, showed fewer anxiety like behaviors in the open field assay. Together, these studies expand on our understanding of environmental influence on SERT KO mice used in translational studies.

scholarly journals Moderation of antidepressant response by the serotonin transporter gene

2009 ◽  
Vol 195 (1) ◽  
pp. 30-38 ◽  
Author(s):  
Patricia Huezo-Diaz ◽  
Rudolf Uher ◽  
Rebecca Smith ◽  
Marcella Rietschel ◽  
Neven Henigsberg ◽  
...  
Keyword(s):  
Serotonin Transporter ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Severe Depression ◽  
Serotonin Transporter Gene ◽  
Transporter Gene ◽  
Antidepressant Response ◽  
Therapeutic Drugs ◽  
Noradrenaline Reuptake ◽  
Antidepressant Effects ◽  
And Gender

BackgroundThere have been conflicting reports on whether the length polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) moderates the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR is modulated by gender, age and other variants in the serotonin transporter gene.AimsTo test the hypothesis that the 5-HTTLPR differently influences response to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline reuptake inhibitor).MethodThe 5-HTTLPR and 13 additional markers across the serotonin transporter gene were genotyped in 795 adults with moderate-to-severe depression treated with escitalopram or nortriptyline in the Genome Based Therapeutic Drugs for Depression (GENDEP) project.ResultsThe 5-HTTLPR moderated the response to escitalopram, with long-allele carriers improving more than short-allele homozygotes. A significant three-way interaction between 5-HTTLPR, drug and gender indicated that the effect was concentrated in males treated with escitalopram. The single-nucleotide polymorphism rs2020933 also influenced outcome.ConclusionsThe effect of 5-HTTLPR on antidepressant response is SSRI specific conditional on gender and modulated by another polymorphism at the 5' end of the serotonin transporter gene.

scholarly journals Common variation at 16p11.2 is associated with glycosuria in pregnancy: findings from a genome-wide association study in European women

2020 ◽  
Vol 29 (12) ◽  
pp. 2098-2106
Author(s):  
Matthew A Lee ◽  
George McMahon ◽  
Ville Karhunen ◽  
Kaitlin H Wade ◽  
Laura J Corbin ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Adverse Outcomes ◽  
Genome Wide Association ◽  
Chromosome 16 ◽  
Parents And Children ◽  
Genome Wide ◽  
Maternal Genotype ◽  
A Genome ◽  
Offspring Genotype

Abstract Glycosuria is a condition where glucose is detected in urine at higher concentrations than normal (i.e. not detectable). Glycosuria at some point during pregnancy has an estimated prevalence of 50% and is associated with adverse outcomes in both mothers and offspring. Little is currently known about the genetic contribution to this trait or the extent to which it overlaps with other seemingly related traits, e.g. diabetes. We performed a genome-wide association study (GWAS) for self-reported glycosuria in pregnant mothers from the Avon Longitudinal Study of Parents and Children (cases/controls = 1249/5140). We identified two loci, one of which (lead SNP = rs13337037; chromosome 16; odds ratio of glycosuria per effect allele: 1.42; 95% CI: 1.30, 1.56; P = 1.97 × 10−13) was then validated using an obstetric measure of glycosuria measured in the same cohort (227/6639). We performed a secondary GWAS in the 1986 Northern Finland Birth Cohort (NFBC1986; 747/2991) using midwife-reported glycosuria and offspring genotype as a proxy for maternal genotype. The combined results revealed evidence for a consistent effect on glycosuria at the chromosome 16 locus. In follow-up analyses, we saw little evidence of shared genetic underpinnings with the exception of urinary albumin-to-creatinine ratio (Rg = 0.64; SE = 0.22; P = 0.0042), a biomarker of kidney disease. In conclusion, we identified a genetic association with self-reported glycosuria during pregnancy, with the lead SNP located 15kB upstream of SLC5A2, a target of antidiabetic drugs. The lack of strong genetic correlation with seemingly related traits such as type 2 diabetes suggests different genetic risk factors exist for glycosuria during pregnancy.

Bioactivities of serotonin transporter mediate antidepressant effects of Acorus tatarinowii Schott

2019 ◽  
Vol 241 ◽  
pp. 111967 ◽  
Author(s):  
Feng-Hong Zhang ◽  
Zhi-Mei Wang ◽  
Yan-Ting Liu ◽  
Ji-Sheng Huang ◽  
Shuang Liang ◽  
...  
Keyword(s):  
Serotonin Transporter ◽  
Antidepressant Effects ◽  
Acorus Tatarinowii

scholarly journals What are maternal effects (and what are they not)?

2009 ◽  
Vol 364 (1520) ◽  
pp. 1107-1115 ◽  
Author(s):  
Jason B Wolf ◽  
Michael J Wade
Keyword(s):  
Maternal Effects ◽  
Niche Construction ◽  
Life History Evolution ◽  
Causal Link ◽  
Ecological Processes ◽  
Maternal Genotype ◽  
Evolutionary Response ◽  
Offspring Genotype ◽  
Definition Of ◽  
Evolutionary Consequences

Maternal effects can play an important role in a diversity of ecological and evolutionary processes such as population dynamics, phenotypic plasticity, niche construction, life-history evolution and the evolutionary response to selection. However, although maternal effects were defined by quantitative geneticists well over half a century ago, there remains some confusion over exactly what phenomena should be characterized as maternal effects and, more importantly, why it matters and how they are defined. We suggest a definition of maternal effects as the causal influence of the maternal genotype or phenotype on the offspring phenotype. This definition differs from some definitions in that it treats maternal effects as a phenomenon, not as a statistical construct. The causal link to maternal genotype or phenotype is the critical component of this definition providing the link between maternal effects and evolutionary and ecological processes. We show why phenomena such as maternal cytoplasmic inheritance and genomic imprinting are distinct genetically from and have different evolutionary consequences than true maternal effects. We also argue that one should consider cases where the maternal effect is conditional on offspring genotype as a class of maternal effects.

scholarly journals The Role of the Serotonin Transporter as a Genetic Risk Factor in the Development of Drug Addiction

2021 ◽  
Author(s):  
◽  
Bridget Williams Brox
Keyword(s):  
Taste Aversion ◽  
Drug Addiction ◽  
Serotonin Transporter ◽  
Conditioned Taste Aversion ◽  
Self Administration ◽  
Bdnf Expression ◽  
Drug Induced ◽  
Psychological Burden ◽  
Genotype Effect ◽  
The Individual

<p>Drug addiction is a ubiquitous phenomenon worldwide that places tremendous financial and psychological burden on societies, families and the individual. Interestingly, only a small percentage of individuals ( 20%), regardless their drug of choice, go on to develop the compulsive behaviours that define drug addiction. Clinical studies have shown that there is a subset of the population with a genetically determined reduction in the serotonin transporter that may increase vulnerability to developing a variety of psychiatric disorders like depression, anxiety and drug addiction.  To investigate the influence of reduced serotonin transporter function in the laboratory we studied the effects of MDMA (‘ecstasy’) and heroin in a genetically altered animal model: the serotonin transporter (SERT) knockout rat. Homozygous (HOM) animals lack SERT function completely while heterozygous (HET) have about 50% SERT function compared to the wild type (WT). Groups of HOM, HET and WT animals completed MDMA or heroin self-administration experiments. A robust genotype effect emerged for animals self-administering MDMA; facilitation of MDMA self-administration was inversely related to SERT function. HOM animals, without exception, reached acquisition criterion significantly faster than the HET animals; HET animals then showed higher acquisition rates compared to the WT animals. In contrast, there were no differences between the genotypes when animals self-administered heroin. To investigate the driving force behind facilitated MDMA self-administration in animals with reduced SERT function locomotor activity and conditioned taste aversion experiments were undertaken. In contrast to the drug self-administration experiments,MDMA induced hyperactivity was positively related to SERT function. Thus, it was significantly reduced in HOM and HET animals compared to the WT. Again, heroin treatment did not produce differences in locomotion between the genotypes. MDMA induced conditioned taste aversion revealed only a main effect of dose with robust conditioned taste aversion for both drug doses, although a trend indicated that HOM animals may have heightened sensitivity to MDMA. However, heroin treatment failed to produce a conditioned taste aversion effect in any of the groups regardless of dose. Beyond the aforementioned behavioural experiments striatal brain tissue from the animals that had previously self-administered MDMA or heroin was analysed via quantitative reverse transcription polymerase chain reaction; five targets were evaluated to quantify drug induced changes in brain derived neurotrophic factor gene expression (BDNF). Several BDNF isoforms (total BDNF, BDNF III and BDNF IV) were significantly increased in animals that had self-administered MDMA; this effect was true across HOM, HET and WT subjects. Comparatively, animals that had self-administered heroin did not show a difference in BDNF expression compared to untreated control animals.  This suite of experiments provides insight into the influence of a compromised serotonergic system on the development of drug addiction. That is, while reduced SERT function does not appear to augment the addictive properties of drugs like heroin there is reason to suspect that it does confer additional susceptibility to developing addiction to drugs like MDMA, highlighting the hypothesis that different classes of addictive substances act through different neurobiological pathways.</p>

A cautionary note on using Mendelian randomization to examine the Barker hypothesis and Developmental Origins of Health and Disease (DOHaD)

2020 ◽  
pp. 1-6
Author(s):  
Shannon D’Urso ◽  
Geng Wang ◽  
Liang-Dar Hwang ◽  
Gunn-Helen Moen ◽  
Nicole M. Warrington ◽  
...  
Keyword(s):  
Cardiometabolic Risk ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Developmental Origins ◽  
Phenotypic Data ◽  
Barker Hypothesis ◽  
Maternal Genotype ◽  
Increased Risk ◽  
Offspring Genotype ◽  
Health And Disease

Abstract Recent studies have used Mendelian randomization (MR) to investigate the observational association between low birth weight (BW) and increased risk of cardiometabolic outcomes, specifically cardiovascular disease, glycemic traits, and type 2 diabetes (T2D), and inform on the validity of the Barker hypothesis. We used simulations to assess the validity of these previous MR studies, and to determine whether a better formulated model can be used in this context. Genetic and phenotypic data were simulated under a model of no direct causal effect of offspring BW on cardiometabolic outcomes and no effect of maternal genotype on offspring cardiometabolic risk through intrauterine mechanisms; where the observational relationship between BW and cardiometabolic risk was driven entirely by horizontal genetic pleiotropy in the offspring (i.e. offspring genetic variants affecting both BW and cardiometabolic disease simultaneously rather than a mechanism consistent with the Barker hypothesis). We investigated the performance of four commonly used MR analysis methods (weighted allele score MR (WAS-MR), inverse variance weighted MR (IVW-MR), weighted median MR (WM-MR), and MR-Egger) and a new approach, which tests the association between maternal genotypes related to offspring BW and offspring cardiometabolic risk after conditioning on offspring genotype at the same loci. We caution against using traditional MR analyses, which do not take into account the relationship between maternal and offspring genotypes, to assess the validity of the Barker hypothesis, as results are biased in favor of a causal relationship. In contrast, we recommend the aforementioned conditional analysis framework utilizing maternal and offspring genotypes as a valid test of not only the Barker hypothesis, but also to investigate hypotheses relating to the Developmental Origins of Health and Disease more broadly.

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