SERT Gene Research Articles

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.

Impact of Serotonin Transporter Absence on Brain Insulin Receptor Expression, Plasma Metabolome Changes, and ADHD-like Behavior in Mice fed a Western Diet.

The impaired function of the serotonin transporter (SERT) in humans has been linked to a higher risk of obesity and type 2 diabetes, especially as people age. Consuming a "Western diet" (WD), which is high in saturated fats, cholesterol, and sugars, can induce metabolic syndrome. Previous research indicated that mice carrying a targeted inactivation of the Sert gene (knockout, KO) and fed a WD display significant metabolic disturbances and behaviors reminiscent of ADHD. These abnormalities might be mediated via a dysfunction in insulin receptor (IR) signaling, which is also associated with adult ADHD. However, the impact of Sert deficiency on IR signaling and systemic metabolic changes has not been thoroughly explored. In this study, we conducted a detailed analysis of locomotor behavior in wild-type (WT) and KO mice fed a WD or control diet. We investigated changes in the blood metabolome and examined, via PCR, the expression of insulin receptor A and B isoforms and key regulators of their function in the brain. Twelve-month-old KO mice and their WT littermates were fed a WD for three weeks. Nuclear magnetic resonance spectroscopy analysis of plasma samples showed that KO mice on a WD had higher levels of lipids and lipoproteins and lower levels of glucose, lactate, alanine, valine, and isoleucine compared to other groups. SERT-KO mice on the control diet exhibited increased brain levels of both IR A and B isoforms, accompanied by a modest increase in the negative regulator ENPP. The KO mice also displayed anxiety-like behavior and reduced exploratory activity in an open field test. However, when the KO animals were fed a WD, the aberrant expression levels of IR isoforms in the KO mice and locomotor behavior were ameliorated indicating a complex interaction between genetic and dietary factors that might contribute to ADHD-like symptoms. Overall, our findings suggest that the lack of Sert leads to a unique metabolic phenotype in aged mice, characterized by dysregulated IR-related pathways. These changes are exacerbated by WD in the blood metabolome and are associated with behavioral abnormalities.

Modified Sijunzi Granules Exhibit Hemostatic Effect by Activating Akt and Erk Signal Pathways via Regulating 5-HT and Its Receptors Levels.

To investigate the hemostatic effect of modified Sijunzi Granules (MSG) in primary immune thrombocytopenia (ITP) zebrafish model and explore the potential mechanism. AB strain wild type zebrafish were treated with simvastatin (6 µmol/L) for 24 h to establish the hemorrhage model (model control group). The zebrafish were treated with MSG at different doses (55.6, 167, and 500 µg/mL), respectively. The hemostatic effect was assessed by examining the intestinal bleeding and hemostatic rate. 5-Hydroxytryptamine (5-HT) content was determined using enzyme-linked immunosorbent assay (ELISA) assay. The expressions of 5-HT2aR, 5-HT2bR, and SERT genes were detected by quantitative real-time polymerase chain reaction(PCR). The protein expressions of protein kinase B (Akt), p-Akt, extracellular regulated protein kinases (Erk), and p-Erk were examined using Western blot analysis. The intestinal bleeding rate was 37%, 40%, and 80% in the 55.6, 167, and 500 µg/mL dose of MSG, respectively, in which 55.6 and 167 µg/mL MSG dose groups were associated with significantly decreased intestinal bleeding rate when compared with the model control group (70%, P<0.05). Significantly higher hemostatic rates were also observed in the 55.6 (54%) and 167 (52%) µg/mL MSG dose groups (P<0.05). MSG increased the 5-HT content and mRNA expression levels of 5-HT2aR, 5-HT2bR, and SERT (P<0.05). In addition, caspase3/7 activity was inhibited (P<0.05). Significant increase in p-Akt and p-Erk was also detected after treatment with MSG (P<0.05). MSG could reduce the incidence and severity of intestinal bleeding in zebrafish by activating MAPK/Erk and PI3K/Akt signal pathways through regulating the levels of 5-HT and its receptors, which may provide evidence for the treatment of ITP.

Regional expression differences of SERT and TSPAN8 in hippocampus, cerebellum and cortex of wild-type young, adult and middle-aged rats

Changes in gene expression with aging are associated with a decline in physical and cognitive abilities. Here, we investigated the changes in mRNA and protein expression of TSPAN8 and SERT in the different parts of the brain for different age group rats. Our protein analysis revealed that aging mainly triggers SERT gene expression in the cerebellum and hippocampus, showing that an increase in mRNA expression correlates with protein expression. For TSPAN8, age-dependent protein increase was observed in the hippocampus and highest expression was observed for adult and middle-aged rats.

Maternal nicotine intoxication before pregnancy induces depressive- and anxiety-like behaviors as well as cognitive deficits in male offspring and correlates with neurobiological changes.

Maternal nicotine use has been suggested to affect the behavior of children and is linked to changes in neurological systems; however, the specific mechanism is yet to be understood. Mice were used to establish a maternal nicotine intoxication model. At postnatal day 60 (adolescent stage), male offspring were tested for behavioral tasks including sucrose preference, open field, elevated plus maze, light/dark box, object recognition, Morris water maze (MWM), and forced swimming. Enzyme-linked immunoassays were used to measure plasma concentrations of neurotransmitters including norepinephrine, dopamine, serotonin, and corticosterone. Serotonin transporter (Sert), brain-derived neurotrophic factor (Bdnf), cAMP response element binding protein (Creb), and phosphorylated (p)Creb mRNA levels were measured using quantitative real-time polymerase chain reaction. Male offspring of nicotine-intoxicated dams had significantly reduced sucrose preference, mobility time in the forced swimming test, and locomotor and exploratory activities. Offspring in the maternal nicotine intoxication group showed increased signs of depressive- and anxiety-like behavior. Recognition memory in the MWM was compromised in these animals. The hippocampal and prefrontal cortical regions showed significant changes in Bdnf, pCreb, and Sert gene expression, whereas CREB mRNA levels were unaffected. Moreover, compared to the controls, neurogenesis and neuronal viability were also reduced in these animals. Prenatal nicotine exposure might affect the hypothalamic-pituitary-adrenal axis and reduce neurogenesis, potentially leading to depressive-like behaviors and cognitive deficiencies in male offspring.

P136 Multidimensional assessment of visceral hypervigilance in patients with IBD

Abstract Background Persons with inflammatory bowel diseases (IBD) can suffer from irritable bowel syndrome (IBS-like) symptoms in the absence of inflammation. Also, the prevalence of anxiety symptoms and disorders is increased in IBD. Both IBS-like and anxiety symptoms impair quality of life and are challenging to treat as well as poorly understood in IBD. Visceral hypervigilance (VH) as a specific form of anxiety and a common feature of disorders of gut-brain interaction may be a relevant symptom in IBD and could relate to IBS-like symptoms. This study aimed at investigating clinical, psychological and biological factors associated with VH in persons with IBD. Methods We used the visceral sensitivity index (VSI) to investigate VH in 308 patients with different states of IBD disease activity (as determined by Harvey Bradshaw Index or partial Mayo Score). We further assessed demographic (age, sex), clinical (disease duration, CRP levels) and psychological (anxiety and depression, HADS) characteristics. Genetic and metabolic parameters related to serotonin metabolism were analyzed in subsamples with active disease (single nucleotide polymorphisms in genes related to serotonin signaling (n=83) and serum tryptophan metabolites (n=70)). We used multiple regression analyses to examine which factors could predict patients’ VH levels and to explore genetic and metabolic predictors of VH. Results The strongest predictors for VH were anxiety, depression and disease activity (all p &amp;lt; .001, Fig.1, left). Explorative analyses revealed polymorphisms in the HTR3A (p = .028) and SERT gene (p = .030) to predict VH (Fig.1, middle). While clinical disease activity was related to VH, there was no association between VH and inflammatory biomarkers or tryptophan metabolites (Fig.1, left and right). Conclusion VH as a specific type of anxiety strongly relates to psychopathology in persons with IBD. Anxiety was found to be the strongest predictor of VH, contributing to a greater extent to VH than disease activity. Possible genetic predispositions of VH should be investigated in larger studies. Screening patients for VH could help to detect disturbances in gut-brain-interactions and improve individualized treatment.

Gut indigenous Ruminococcus gnavus alleviates constipation and stress-related behaviors in mice with loperamide-induced constipation.

Refractory constipation is the most severe form of constipation, and its etiology remains unknown. The symptoms of constipation occur repeatedly, which brings great pain to the patient's body and psychology. Accumulating studies suggest that constipation patients present a significant dysbiosis of the gut microbiota compared with healthy individuals. In this study, we analyzed the gut microbiota composition of fresh feces and accumulated feces (old feces) of patients with refractory constipation and found that there was a significant difference between them. Through a mouse model of loperamide-induced constipation, it was proved that the old feces of patients with refractory constipation could aggravate the constipation symptoms in mice, while the fresh feces could alleviate the symptoms, which is consistent with the effect of feces from healthy volunteers in a mouse model of loperamide-induced constipation. We identified an indigenous strain Ruminococcus gnavus (R. gnavus), which is highly enriched in the fresh feces of patients with refractory constipation, and found that oral administration of R. gnavus could effectively improve the constipation symptoms in mice with constipation induced by loperamide and fecal bacteria transplanted from patients with constipation and significantly improve the stress-related behaviors of mice. This result may be related to the regulation of intestinal muc2, c-kit, sert and other gene expression by R. gnavus and the control of somatostatin (SS) and motilin (MTL) production. Our results suggest that gut microbe intervention with indigenous strains such as R. gnavus is a potential and promising alternative for the treatment of constipation, especially for refractory constipation.

Effects of polymorphisms of COMT, TPH1 and SERT gene mutations on perceived childhood trauma in suicide attempters with eating disorders

Effects of polymorphisms of COMT, TPH1 and SERT gene mutations on perceived childhood trauma in suicide attempters with eating disorders

Taking risks to feel excitement: Detailed personality profile and genetic associations

This study mapped the personality and genetics of risky excitement-seekers focusing on skydiving behavior. We compared 298 skydivers to 298 demographically matched controls across the NEO Personality Inventory-3 domains, facets, and 240 items. The most significant item-level effects were aggregated into a poly-item score of skydiving-associated personality markers (Study 1), where higher scores describe individuals who enjoy risky situations but have no self-control issues. The skydiving-associated personality marker score was associated with greater physical activity, higher rate of traumatic injuries, and better mental health in a sample of 3558 adults (Study 2). From genetic perspective, we associated skydiving behavior with 19 candidate variants that have previously been linked to excitement-seeking (Study 1). Polymorphisms in the SERT gene were the strongest predictors of skydiving, but the false discovery rate-adjusted (FDR-adjusted) p-values were non-significant. In Study 2, we predicted the skydiving-associated personality marker score and E5: Excitement-seeking from multiple risk-taking polygenic scores, using publicly available summary data from genome-wide association studies. While E5: Excitement-seeking was most strongly predicted by general risk tolerance and risky behaviors’ polygenic scores, the skydiving-associated personality marker score was most strongly associated with the adventurousness polygenic scores. Phenotypic and polygenic scores associations suggest that skydiving is a specific—perhaps more functional—form of excitement-seeking, which may nevertheless lead to physical injuries.

GENETIC DETERMINATION OF POSTOPERATIVE INTESTINAL PARESIS IN THE BACKGROUND OF PERITONITIS

Postoperative intestinal paresis remains an urgent problem of abdominal surgery, since it is one of the most common postoperative complications in terms of frequency. In most studies, the violation of the motor function of the intestine after surgery on the hollow organs of the digestive system is considered as a pathological process, is a consequence of postoperative peritonitis. The paper presents data on the relationship between the variants of the SERT gene, which regulates the reuptake of serotonin, with the concentration in the blood plasma and the likelihood of postoperative intestinal paresis and peritonitis. This made it possible not only to predict the occurrence of postoperative disorders of the motor-evacuation function of the intestine, but also to improve the algorithms for their prevention and pathogenetically justified treatment. It has been established that it is with the SS-genotype that postoperative disorders of the motor-evacuation function of the intestine occur more often, which lead to peritonitis. This leads to a change in treatment tactics in such patients. If these unfavorable genotype variants are found for surgery in such patients, we consider it expedient to expand the indications for intestinal intubation even without intraoperative manifestations of its paresis. We have proposed a technique in which nasointestinal intubation of the small intestine is first performed, which is necessary for the main stage of the operation. If it is necessary to withdraw the stoma, the indications for which in patients with unfavorable genotype variants are considered appropriate to expand, the intubation probe is cut off at the first opening, which is placed in the stomach, and the other end is withdrawn through the stoma. This greatly simplifies the technique of bowel intubation, avoids various complications associated with retrograde intubation, and, first of all, wound infection. Studies indicate a high risk of developing postoperative peritonitis in surgical patients who, after surgical interventions on the digestive organs, had pronounced disorders of the motor-evacuation function of the intestine. Improved algorithms for the treatment of such patients make it possible to significantly reduce the risk of developing postoperative intestinal paresis and peritonitis, and, if they occur, to effectively eliminate their manifestations.

Genes acting in synapses and neuron projections are early targets of selection during urban colonization.

When a species colonizes an urban habitat, differences in the environment can create novel selection pressures. Successful colonization will further lead to demographic perturbations and genetic drift, which can interfere with selection. Here, we test for consistent urban selection signals in multiple populations of the burrowing owl (Athene cunicularia), a species that colonized South American cities just a few decades ago. We sequenced 213 owls from three urban-rural population pairs and performed a genome-wide comparison of urban against rural birds. We further studied genome-wide associations with flight initiation distance, a measure of harm avoidance in which urban and rural birds are known to differ. Based on four samples taken over nine years from one of the urban populations, we investigated temporal allele frequency changes. The genomic data were also used to identify urban-specific signatures of selective sweeps. Single genomic sites did not reach genome-wide significance for any association. However, a gene-set analysis on the strongest signals from these four selection scans suggests a significant enrichment of genes with known functions related to synapses and neuron projections. We identified 98 genes predominantly expressed in the brain, of which many may play a role in the modulation of brain connectivity and consequently in cognitive function and motivational behaviour during urbanization. Furthermore, polymorphisms in the promoter region of the synaptic SERT gene - one of the two candidates known to correlate with urban colonization in birds - associated with the habitat in which individuals lived (urban vs. rural).

LncRNA XIST modulates 5-hydroxytrytophan-induced visceral hypersensitivity by epigenetic silencing of the SERT gene in mice with diarrhea-predominant IBS

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a prevalent gastrointestinal disorder with a high incidence in children. The role of long non-coding RNAs (lncRNAs) in gastrointestinal diseases has been previously highlighted. Nevertheless, the underlying regulatory mechanism of lncRNA X inactivate-specific transcript (XIST) in IBS-D requires further studies. Thus, the present study was conducted with the main objective of elucidating the underlying mechanism of lncRNA XIST in visceral hypersensitivity in IBS-D. An in vivo mouse model of IBS-D was constructed via rectal perfusion of acetic acid. Next, in order to evaluate the effect of lncRNA XIST on the development of visceral hypersensitivity in IBS-D, different vector plasmids were injected into mice along with rectal mucosal epithelial cells, followed by the measurement of abdominal withdrawal reflex (AWR) score, counts of peristaltic wave, abdominal wall contraction and defecation particles. Furthermore, luciferase reporter assay, FISH, RIP and ChIP assays were conducted to determine the interactions between lncRNA XIST and SERT. Subsequently, MS-PCR was adopted to test the methylation level of SERT promoter. 5-hydroxytrytophan (HT) content in rectal tissues was detected using immunohistochemistry. The IBS-D mouse models presented with a high expression of lncRNA XIST along with low expression of SERT. LncRNA XIST was observed to recruit methylase DNMT1, DNMT3A and DNMT3B to promote SERT promoter methylation, reducing its expression. Restoration of lncRNA XIST resulted in increased AWR score, counts of peristaltic wave, abdominal wall contraction and defecation particles along with stimulated 5-HT expression and SERT methylation level, while downregulation of lncRNA XIST reversed these effects. In conclusion, the key findings from our study indicated that lncRNA XIST acts as a regulator in 5-HT-induced visceral hypersensitivity in mice with IBS-D, providing a new insight into the regulatory effect of lncRNA XIST and its epigenetic diagnostic and therapeutic properties in IBS-D.

Anatomical and behavioral impact of a lentiviral tool tapping onto hippocampal serotonin reuptake in rats.

We aimed at the further characterization of rats in which SERT gene silencing was achieved by hippocampal injection of a lentiviral vector, carrying three si-RNA to block SERT mRNA at 66% of normal levels. Improved self-control and reduced restlessness were already demonstrated in these rats. Present further studies consisted of male adult rats, bilaterally inoculated within the hippocampus; control rats received lentivirus particles inactivated with heat. Both groups were maintained in isolation for 5months, starting from inoculation. Neurochemical changes were studied by proton magnetic resonance spectroscopy (1H-MRS): we found increased hippocampal viability and bioenergetic potential; however, rats showed a behaviorally depressive pattern, also characterized by enhanced affiliation. Based on the extent of such effects, the whole lenti-SERT group was divided into two subgroups, termed intermediate- and extreme- phenotype profiles. While all rats had a widespread modification within dorsal/ventral striatum, amygdala, and hypothalamus, only the former subgroup showed an involvement of Raphé medialis, while, for the latter subgroup, an increase of SERT within hippocampus was unexpectedly caused. Within the less-affected "intermediate" rats, hippocampal 5-HT7 receptors were down-modulated, and also similarly within substantia nigra, septum, and neocortex. This picture demonstrates that additional rather than fewer neurobiological changes accompany a lower phenotypic expression. Overall, tapping hippocampal SERT affected the balance between habits versus strategies of coping by promoting morphogenetic processes indicative of a serotonergic fiber plasticity. Supplementary studies about serotonergic dynamics and neurogenesis within fronto-striatal circuits are needed.

Serotonin transporter untranslated regions influence mRNA abundance and protein expression

The serotonin transporter (SERT, SLC6A4) is a Na+-dependent transporter that regulates the availability of serotonin (5-HT, 5-hydroxytryptamine), a key neurotransmitter and hormone in the brain and the intestine. The human SERT gene consists of two alternate promoters that drive expression of an identical SERT protein. However, there are different mRNA transcript variants derived from these two promoters that differ in their 5′ untranslated region (5′UTR), which is the region of the mRNA upstream from the protein-coding region. Two of these transcripts contain exon-1a and are abundant in neuronal tissue, whereas the third transcript contains exon-1c and is abundant in the intestine. The 3′UTR is nearly identical among the transcripts. Current studies tested the hypothesis that the UTRs of SERT influence its expression in intestinal epithelial cells (IECs) by controlling mRNA or protein levels. The SERT UTRs were cloned into luciferase reporter plasmids and luciferase mRNA and activity were measured following transient transfection of the UTR constructs into the model IEC Caco-2. Luciferase activity and mRNA abundance were higher than the empty vector for two of the three 5′UTR variants. Calculation of translation index (luciferase activity divided by the relative luciferase mRNA level) revealed that the exon-1a containing 5′UTRs had enhanced translation when compared to the exon-1c containing 5′UTR which exhibited a low translation efficiency. Compared to the empty vector, the SERT 3′UTR markedly decreased luciferase activity. In silico analysis of the SERT 3′UTR revealed many conserved potential miRNA binding sites that may be responsible for this decrease. In conclusion, we have shown that the UTRs of SERT regulate mRNA abundance and protein expression. Delineating the molecular basis by which the UTRs of SERT influence its expression will lead to an increased understanding of post-transcriptional regulation of SERT in GI disorders associated with altered 5-HT availability.

Changes in sexual performance and biochemical characterisation of functional neural regions: A study in serotonin transporter knockout male rats.

To explore the correlation between SERT expression and sexual activities and seek the possible mechanism of SERT in regulating ejaculations, we analysed the sexual activities and biochemical characteristics of five measured neural regions in three rat genotypes (SERT-/- , SERT+/- and SERT+/+ ). The results showed the SERT-/- group showed fewer ejaculations and a longer ejaculation latency than the SERT+/+ group, while the SERT+/- group did not differ significantly from the SERT+/+ group in sexual performance. In addition, the SERT-/- group showed an almost complete absence of SERT mRNA and protein expression in all measured regions. In the SERT+/- group, the SERT mRNA and SERT protein expressions were downregulated by approximately 50% and 35%, respectively, compared to the SERT+/+ group. The SERT-/- group had the highest 5-HT levels, and the 5-HT level in the SERT+/- group was between the other two groups. Besides, the 5-HT levels differed in almost all measured regions of the three groups. Therefore, our study confirmed that SERT played a key role in sexual performance. A certain amount of SERT protein may be critical to normal sexual performance. Hence, Polymorphisms of the SERT gene should still be highlighted for ejaculation regulation research.

The serotonin transporter gene could play a role in anti-predator behaviour in a forest passerine

Elucidating associations between behavioural variation and genes may help to understand the co-existence of different behavioural phenotypes in natural populations. In birds, two main candidate genes are known to affect exploratory and risk-taking behaviour through the neurotransmitter system: the dopamine receptor D4 gene (DRD4) and the serotonin transporter gene (SERT/SLC6A4). In a small passerine bird, the great tit (Parus major), anti-predator responses (hissing or non-hissing behavioural type) towards a nest predator differ consistently between individuals. As defensive anti-predator behaviours are likely related to variations in neurotransmitter systems, we tested the associations between polymorphisms of the two candidate genes (SERT and DRD4) and the propensity to give hissing calls towards a nest predator in incubating female great tits. We found that acoustic anti-predator responses in wild birds were linked to a single-nucleotide polymorphism in the SERT gene (SNP187 in exon 1), but not in the DRD4 gene. The polymorphism in the SERT gene explains about 16% of the total variance in hissing behaviour. However, as the sample size in this study is quite small, these results are preliminary and should be replicated in future studies.

SA45 - AFFECTIVE TEMPERAMENT AND DEPRESSIVE SYMPTOMS IN OBESE INDIVIDUALS IN THE CONTEXT OF SEROTONERGIC TRANSCRIPTIONAL GENE POLYMORPHISMS

Background Patients with obesity experience many psychological burdens. Some of them result directly from the load that jets excessive weight. Nevertheless, it seems that the susceptibility of obese people to accompanying mental disorders can be ingested not only by the environment, but also genetically. The aim of this work was to determine the correlation of the genetic aspects of serotoninergic (SERT, 5-HT2A) transmission with the severity of depressive symptoms and the affective temperament profile in subjects with simple obesity. Methods The study included 506 patients with simple obesity who were excluded secondary causes of obesity and significant mental illness. Clinical, psychological and genetic analyzes were performed. To assess the severity of depressive symptoms, Beck Depression Inventory and the Hamilton Depression Scale were used. Affective temperament was assessed using the TEMPS-A questionnaire. Polymorphism of serotonin transporter (SERT 44-bp insertion/deletion) and serotonin receptor 2 A type (1438 G/A) were evaluated as potential genetic markers of psychological factors. Results The long allele of SERT gene was associated with significantly higher BMI and more pronounced depressive, cyclothymic and hyperthymic dimensions of affective temperament. Interestingly, these subjects obtained the lowest scores of both scales, which measured the severity of depressive symptoms. Adenine homozygotes in examined 5-HT2A polymorphism were characterized by higher BMI and more pronounced anxious and, in particular, hyperthymic dimension of temperament. Carriers of particular polymorphisms in this gene did not differ significantly in the clinical scale evaluating the severity of depressive symptoms. Discussion Polymorphisms of both examined genes revealed correlations in affective temperamental dimensions. Acknowledgments in the SERT polymorphism seems to play a more important role in the regulation of reactive depressive symptoms.

Short-Term Environmental Stimulation Spatiotemporally Modulates Specific Serotonin Receptor Gene Expression and Behavioral Pharmacology in a Sexually Dimorphic Manner in Huntington's Disease Transgenic Mice.

Huntington’s disease (HD) is a neurodegenerative disorder caused by a tandem repeat mutation encoding an expanded polyglutamine tract in the huntingtin protein, which leads to cognitive, psychiatric and motor dysfunction. Exposure to environmental enrichment (EE), which enhances levels of cognitive stimulation and physical activity, has therapeutic effects on cognitive, affective and motor function of transgenic HD mice. The present study investigated gene expression changes and behavioral pharmacology in male and female R6/1 transgenic HD mice at an early time-point in HD progression associated with onset of cognitive and affective abnormalities, following EE and exercise (wheel running) interventions. We have demonstrated changes in expression levels of the serotonin (5-HT) receptor Htr1a, Htr1b, Htr2a and Htr2c genes (encoding the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors, respectively) in HD brains at 8 weeks of age, using quantitative real-time PCR. In contrast, expression of the serotonin transporter (SerT, also known as 5-HTT or Slc6a4) was not altered in these brains. Furthermore, we identified region-specific, sex-specific and environmentally regulated (comparing EE, exercise and standard housing conditions) impacts on gene expression of particular 5-HT receptors, as well as SerT. For example, SerT gene expression was upregulated by exercise (wheel running from 6 to 8 weeks of age) in the hippocampus. Interestingly, when EE was introduced from 6 to 8 weeks of age, Htr2a gene expression was upregulated in the cortex, striatum and hippocampus of male mice. EE also rescued the functional activity of 5-HT2 receptors as observed in the head-twitch test, reflecting sexually dimorphic effects of environmental stimulation. These findings demonstrate that disruption of the serotonergic system occurs early in HD pathogenesis and, together with previous findings, show that the timing and duration of environmental interventions are critical in terms of their ability to modify gene expression. This study is the first to show that EE is able to selectively enhance both gene expression of a neurotransmitter receptor and the functional consequences on behavioral pharmacology, and links this molecular modulation to the therapeutic effects of environmental stimulation in this neurodegenerative disease.

Brain hyperserotonemia causes autism-relevant social deficits in mice

BackgroundHyperserotonemia in the brain is suspected to be an endophenotype of autism spectrum disorder (ASD). Reducing serotonin levels in the brain through modulation of serotonin transporter function may improve ASD symptoms.MethodsWe analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter (Sert) knockout mice.ResultsSocial deficits were observed in both heterozygous knockout mice (HZ) and homozygous knockout mice (KO), but increases in general anxiety were only observed in KO mice. Two weeks of dietary restriction of the serotonin precursor tryptophan ameliorated both brain hyperserotonemia and ASD-relevant social deficits in Sert HZ and KO mice. The expression of rather distinct sets of genes was altered in Sert HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in Sert HZ and KO mice was associated with alterations in the expression of genes involved in signal transduction pathways initiated by changes in extracellular serotonin or melatonin, a derivative of serotonin. Only expression of the AU015836 gene was altered in both Sert HZ and KO mice. AU015836 expression and ASD-relevant social deficits normalized after dietary tryptophan restriction.ConclusionsThese findings reveal a Sert gene dose-dependent effect on brain hyperserotonemia and related behavioral sequelae in ASD and a possible therapeutic target to normalize brain hyperserotonemia and ASD-relevant social deficits.

Changes in Gene Expression Profiles in Adult Rat Brain Structures after Neonatal Action of Dipeptidyl Peptidase-IV Inhibitors

Background: Previous studies have shown the development of emotional and motivational disorders, such as anxiety-depression-like disorders with increased aggression in adolescent and adult Wistar rats, occurs after neonatal exposure to the dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5) inhibitors diprotin A and sitagliptin (postnatal days 5–18). Methods: In this study, using real-time PCR, we evaluated changes in the gene expression of serine protease DPP-IV and prolyl endopeptidase (PREP, EC 3.4.21.26; dpp4 and prep genes), monoamine oxidase А (maoA) and B (maoB), and serotonin transporter (SERT; sert) in the brain structures from 3-month-old rats after postnatal action of DPP-IV inhibitors diprotin A and sitagliptin. Results: Dpp4, sert, and maoB gene expression increased and maoA gene expression changed with a tendency to increase in the striatum of rats with neonatal sitagliptin action. The increase of maoA gene expression was also shown in the amygdala. An increase in prep gene expression was found in the striatum of rats with the neonatal action of diprotin A, and a decrease in maoB gene expression was observed in the amygdala. We detected a significant downward trend in sert gene expression in the frontal cortex and amygdala, as well as a tendency to increase in maoA gene expression in the hypothalamus. Discussion: These findings suggest that changes in the expression of the abovementioned genes are associated with the development of anxiety and depression, with increased aggression caused by the neonatal action of diprotin A and sitagliptin.