Modulation of Serotonin-Related Genes by Extracellular Vesicles of the Probiotic Escherichia coli Nissle 1917 in the Interleukin-1ß-Induced Inflammation Model of Intestinal Epithelial Cells.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition involving dysregulated immune responses and imbalances in the gut microbiota in genetically susceptible individuals. Current therapies for IBD often have significant side-effects and limited success, prompting the search for novel therapeutic strategies. Microbiome-based approaches aim to restore the gut microbiota balance towards anti-inflammatory and mucosa-healing profiles. Extracellular vesicles (EVs) from beneficial gut microbes are emerging as potential postbiotics. Serotonin plays a crucial role in intestinal homeostasis, and its dysregulation is associated with IBD severity. Our study investigated the impact of EVs from the probiotic Nissle 1917 (EcN) and commensal E. coli on intestinal serotonin metabolism under inflammatory conditions using an IL-1ß-induced inflammation model in Caco-2 cells. We found strain-specific effects. Specifically, EcN EVs reduced free serotonin levels by upregulating SERT expression through the downregulation of miR-24, miR-200a, TLR4, and NOD1. Additionally, EcN EVs mitigated IL-1ß-induced changes in tight junction proteins and oxidative stress markers. These findings underscore the potential of postbiotic interventions as a therapeutic approach for IBD and related pathologies, with EcN EVs exhibiting promise in modulating serotonin metabolism and preserving intestinal barrier integrity. This study is the first to demonstrate the regulation of miR-24 and miR-200a by probiotic-derived EVs.

Chronic social defeat stress induces anxiety-like behaviors via downregulation of serotonin transporter in the prefrontal serotonergic system in mice.

The serotonergic (5-HTergic) system is closely involved in the pathophysiology of mood and anxiety disorders and the responsibility of this system may differ for each symptom. In this study, we examined the relationship between the dysfunction of the 5-HTergic system and abnormal behaviors in the social defeat stress model, an animal model of mood and anxiety disorders and in mice with knockdown of Slc6a4, the gene encoding SERT. Monoamine content, serotonin (5-HT) release, 5-HT uptake, 5-HT transporter (SERT) protein levels, and behaviors were investigated in mice subjected to chronic social defeat stress and in mice with knockdown of Slc6a4, in 5-HTergic neurons projecting to the prefrontal cortex (PFC). Furthermore, DNA methylation of Slc6a4 was examined in mice subjected to chronic social defeat stress. Increased turnover, increased extracellular basal levels, decreased release and decreased uptake of 5-HT, and decreased SERT protein levels were observed in the PFC of the stressed mice. The decreased 5-HT uptake correlated with anxiety-like behavior characterized by decreased time spent in the open arms of the elevated plus maze. DNA methylation was increased in the CpG island of Slc6a4 in 5-HTergic neurons projecting to the PFC of the stressed mice. Similar to the stressed mice, mice with Slc6a4 knockdown in 5-HTergic neurons projecting to the PFC also showed decreased release and uptake of 5-HT in the PFC and increased anxiety-like behavior. Chronic stress may induce anxiety due to dysfunction in the prefrontal 5-HTergic system via decreased SERT expression in the PFC.

The Shaggy Dog Story of Enteric Signaling: Serotonin, a Molecular Megillah.

Historically and quantitatively, the enteric site of serotonin (5-HT) storage has primacy over those of any other organ. 5-HT, by the name of "enteramine", was first discovered in the bowel, and the gut produces most of the body's 5-HT. Not only does the bowel secrete 5-HT prodigiously but it also expresses a kaleidoscopic abundance of 5-HT receptors. The larger of two enteric 5-HT stores is mucosal, biosynthetically dependent upon tryptophan hydroxylase1 (TPH1), and located in EC cells. Mechanical stimuli, nutrients, luminal bacteria, and neurotransmitters such as acetylcholine and norepinephrine are all able to stimulate EC cells. Paracrine actions of 5-HT allow the mucosa to signal to neurons to initiate peristaltic and secretory reflexes as well as to inflammatory cells to promote intestinal inflammation. Endocrine effects of 5-HT allow EC cells to influence distant organs, including bone, liver, and endocrine pancreas. The smaller enteric 5-HT store is biosynthetically dependent upon TPH2 and is located within a small subset of myenteric neurons. 5-HT is responsible for slow excitatory neurotransmission manifested primarily in type II/AH neurons. Importantly, neuronal 5-HT also promotes enteric nervous system (ENS) neurogenesis, both pre- and postnatally, through 5-HT2B and especially 5-HT4 receptors. The early birth of serotonergic neurons allows these cells to function as sculptors of the mature ENS. The inactivation of secreted 5-HT depends on transmembrane transport mediated by a serotonin transporter (SERT; SLC6A4). The importance of SERT in control of 5-HT's function means that pharmacological inhibition of SERT, as well as gain- or loss-of-function mutations in SLC6A4, can exert profound effects on development and function of the ENS. Extra-enteric, TPH1-derived 5-HT from yolk sac and placenta promotes neurogenesis before enteric neurons synthesize 5-HT and contribute to ENS patterning. The impressive multi-functional nature of enteric 5-HT has made the precise identification of individual physiological roles difficult and sometimes controversial.

Combined In Silico, Ex Vivo, and In Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Neuro- and Cardioprotective and Antidepressant Effects.

Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepressants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17), a recently designed thiadiazine derivative with putative neuro- and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c-Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT3 and 5-HT1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT3 and 5-HT1A receptors, respectively. L-17 robustly increased c-Fos immunoreactivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT3 and 5-HT1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro- and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs.

Effect of Tongxie Yaofang on Expressions of Colon SERT and Liver 5-HT2AR Proteins in Rats with Ulcerative Colitis Model of Liver Stagnation and Spleen Deficiency / 中国实验方剂学杂志

Objective:To observe the effect of Tongxie Yaofang on the expressions of colon serotonin transporter （SERT）， liver 5-hydroxytryptamine_2A receptor （5-HT_2AR） protein， serum 5-HT and inflammatory factors in ulcerative colitis （UC） model rats of liver stagnation and spleen deficiency， in order to explore the basis of syndrome of liver stagnation and spleen deficiency and the intervention mechanism of Tongxie Yaofang. Method:Fifty male SD rats were randomly divided into blank control group， model group， high， medium and low-dose Tongxie Yaofang group （10，5，2.5 g·kg^-1）， and salazosulacil group （0.3 g·kg^-1）. The ulcerative colitis model of liver depression and spleen deficiency was established by 2，4，6-trinitrobenzene sulfonic acid （TNBS）/ethanol solution enema + restraint stress + diet loss. After successful modeling， the samples were collected after 21 days of drug intervention. Htoxylin eosin （HE） staining and oil red staining were used to observe the pathological changes of colon and liver in each group. Serum interleukin-6 （IL-6）， IL-9， 5-HT and superoxide dismutase （SOD） were detected by enzyme linked immunosorbent assay （ELISA）. Protein expressions of SERT in the colons and 5-HT_2AR in liver of rats were detected by Western blot. Result:Compared with the normal group， obvious ulcers were formed in the colon and lipid droplets in the liver increased in the model group， serum levels of IL-6， IL-9 and 5-HT in the model group increased， while the level of SOD decreased （<italic>P</italic><0.05）. The protein expression of SERT in colon decreased， whereas the protein expression of 5-HT_2AR in liver increased （<italic>P</italic><0.05）. Compare with model group， the pathological damage of colon was improved， and the formation of lipid droplets in liver was reduced in high， medium-dose Tongxie Yaofang groups and sulfasalazine group. The serum levels of IL-6， IL-9 and 5-HT decreased， while the level of SOD increased in Tongxie Yaofang group and sulfasalazine group （<italic>P</italic><0.05）. The protein expression of SERT in colon increased in high，low-dose Tongxie Yaofang groups and sulfasalazine group， and the protein expression of 5-HT_2AR in liver decreased in medium， low dose Tongxie Yaofang groups and sulfasalazine group （<italic>P</italic><0.05）. Conclusion:Tongxie Yaofang may reduce the content of 5-HT， and regulate the intestinal motility and sensory system by up-regulating the expression of SERT in the colon， inhibit the expressions of IL-6，IL-9 and other inflammatory factors， and play an anti-inflammatory role， reduce the content of 5-HT and the expression of 5-HT_2AR in the liver， increase the level of SOD， regulate emotion and lipid metabolism in the liver， and then exert the intervention effect on ulcerative colitis with liver depression and spleen deficiency on the whole.

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 5 months, 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.

Effect of citalopram on miRNA-16/serotonin transporter pathway in peripheral blood of patients with depression / 上海交通大学学报（医学版）

Objective • To discuss the effects of citalopram on miRNA-16/serotonin transporter (SERT) pathway in peripheral blood of the patients with depression. Methods • Forty-five patients with depression without medication (untreated group), 32 patients with depression treated with medicine(drug treated group) and 32 healthy people (control group) were enrolled in the study. Hamilton Depression Scale-17 items were used to evaluate the depressive symptoms. The expression level of plasma miRNA-16 was detected by fluorescence quantitative PCR, and the level of SERT protein in platelets was detected by Western blotting. Fourteen of the baseline patients who were treated with citalopram were followed up for 2 months. After the follow-up, the evaluation of HAMD-17, the detection of miRNA-16 and SERT protein were conducted. Results • There was no significant difference in the expression level of plasma miRNA-16 among the three groups (F=0.421, P=0.657). There was no significant difference of SERT protein expression in the platelets among the three groups (F=0.112, P=0.894). The follow-up study showed that the HAMD-17 score decreased after 2 months (Z=.3.187, P=0.001), the average expression level of plasma miRNA-16 increased (t=2.455, P=0.032), and the expression of SERT protein in the platelets did not change (t=.0.750, P=0.470) in 14 patients who were treated with citalopram. Conclusion • Citalopram, a serotonin reuptake inhibitor, can down-regulate the expression of plasma miRNA-16 in patients with depression, and the decrease of the platelet serotonin is not caused by the decrease of SERT protein on platelet membrane, but may be related to the decrease of the SERT function.

Helicid Ameliorates Learning and Cognitive Ability and Activities cAMP/PKA/CREB Signaling in Chronic Unpredictable Mild Stress Rats.

Helicid (4-formylphenyl-O-ß-D-allopyranoside), an active component found in seeds from the Chinese herb Helicia nilagirica, has been reported to exert sedative, analgesic, hypnotic and antidepressant effects. The present study was designed to evaluate the antidepressant, learning and cognitive improvement effects of helicid in a chronic unpredictable mild stress (CUMS) model of depression in rats and to explore cAMP/protein kinase A (PKA)/cAMP response element-binding (CREB) signaling pathway. Sprague-Dawley rats were randomly assigned to six groups (n = 10): control; CUMS; CUMS + fluoxetine (5 mg/kg) and CUMS + helicid at 8, 16 and 32 mg/kg. All rats were subjected to 12 weeks of CUMS protocols and drug administration during the last 6 weeks of CUMS. Our results showed that helicid, at a dose of 32 mg/kg, significantly reversed decreases in body weight and sucrose consumption, increased the distance and number of crossings in the open-field test (OFT), reduced immobility times in the forced swimming test (FST) and improved spatial memory in the Morris water maze (MWM); all of these effects had been induced by CUMS paradigm. Immunohistochemistry showed that administration of helicid could promoted the proliferation of neurons in the hippocampal CA1 and dentate gyrus (DG) regions. CUMS rats treated with helicid had dramatically decreased protein levels of serotonin transporters (SERTs). In addition, CUMS resulted in a significant reduction in the expression of cAMP, PKA C-α and p-CREB, each of which were partially attenuated by helicid administration. These results indicated that helicid could improve depressive behaviors, learning and cognitive deficits and increase hippocampal neurogenesis, which may be mediated by the regulation of SERTs, activation of the cAMP/PKA/CREB signaling pathway and upregulation of p-CREB levels in hippocampal.

Neonatal fluoxetine exposure modulates serotonergic neurotransmission and disturb inhibitory action of serotonin on food intake.

The neurotransmitter serotonin (5-HT) acts as an important regulator of the critical neurodevelopmental processes and thus alterations in 5-HT signaling early promotes permanent structural and functional changes in brain. The selective serotonin reuptake inhibitors (SSRIs), as fluoxetine and citalopram, blocking serotonin transporter (SERT) at the presynaptic neuron, which regulates extracellular 5-HT levels. Evidence suggests that the exposure to SSRIs in the neurodevelopmental period may alters 5-HT signaling sensitivity on food intake control. The aim of the present study was to evaluate the effects of neonatal exposure to fluoxetine on molecular and cellular components of the serotonergic system and food intake control in young animals. Methods: The animals were divided according to experimental manipulation, Fluoxetine Group (FG): male pups received application of fluoxetine (10 mg/kg, 10 µL/g) and Saline Group (SG): male pups received saline application (0.9% NaCl, 10 µL/g), both throughout lactation (PND1-PND21). They evaluated body weight, food intake, SERT gene and protein expression, serotonin content in the hypothalamus. The neonatal exposure to fluoxetine promoted reduction in body weight, disturb the serotonin hypophagic response, and increase the serotonin and SERT hypothalamic in young animals. We conclude that the changes of components of the serotonergic system by neonatal exposure to fluoxetine may be responsible for disturb the inhibitory action of serotonin on food intake.

Association between SERT insertion/deletion polymorphism and the risk of irritable bowel syndrome: A meta-analysis based on 7039 subjects.

PURPOSE: We performed this study to better assess the relationship between serotonin transporter (SERT) insertion/deletion polymorphism and the risk of irritable bowel syndrome (IBS). METHODS: Eligible studies were searched in PubMed, Medline, Embase and CNKI. A total of 27 studies with 7039 participants were analyzed. RESULTS: Significant association with the risk of IBS was detected for the SERT insertion/deletion polymorphism in additive comparison (p < 0.0001). Further subgroup analyses according to ethnicity of participants revealed that the SERT insertion/deletion polymorphism was significantly associated with the risk of IBS in Asians (dominant model: p = 0.001; recessive model: p = 0.0003; allele model: p = 0.001) and Caucasians (dominant model: p = 0.04; additive model: p < 0.0001). When we stratified available data according to type of disease, we found that the SERT insertion/deletion polymorphism was significantly correlated with the risk of constipation predominant IBS (IBS-C) in recessive comparison (p = 0.04). However, no positive results were detected in the diarrhea predominant IBS (IBS-D) and mixture of diarrhea and constipation IBS (IBS-M) subgroups. CONCLUSIONS: Our findings indicated that the SERT insertion/deletion polymorphism may serve as a genetic biomarker of IBS in Asians and Caucasians.

Does fluoxetine exposure affect hypoxia tolerance in the Gulf toadfish, Opsanus beta?

Due to ineffective wastewater treatment technologies, pharmaceuticals such as the selective serotonin reuptake inhibitors (SSRIs)-a common class of antidepressants which inhibit the serotonin transporter (SERT)-can be found in surface waters and marine receiving waters near wastewater effluents. Understanding how exposure to these chemicals might impact non-target organisms, especially combined with other environmental stressors like hypoxia, is essential in order to thoroughly evaluate environmental risk. It was hypothesized that both acute and chronic exposure to the SSRI fluoxetine (FLX) would interfere with the metabolic hypoxia response of the Gulf toadfish, Opsanus beta. Here we demonstrate that acute intraperitoneal treatment with 50 µg g-1 FLX significantly reduces the regulation index, or degree of metabolic regulation, in toadfish. Acute FLX exposure significantly reduced SERT mRNA expression in the first and third gill arches, but mRNA expression was not affected in heart tissues or in the second gill arch. In contrast, the regulation index was unaffected by 14-17 day waterborne FLX exposure to environmentally relevant (0.01 µg L-1) and approximately 1000-fold higher (8.5 µg L-1) concentrations. However, the higher concentration was sufficient to induce a systemic elevation in plasma serotonin concentrations. Chronic FLX exposure did not alter SERT mRNA expression in heart or gill tissues. The results of this study implicate the involvement of 5-HT pathways in hypoxia tolerance but demonstrate that current environmental levels of FLX are insufficient to impair the metabolic hypoxia response in marine fish.

Effects of N-Alkyl-4-Methylamphetamine Optical Isomers on Plasma Membrane Monoamine Transporters and Abuse-Related Behavior.

4-Methylamphetamine (4-MA) is an emerging drug of abuse that acts as a substrate at plasma membrane transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), thereby causing nonexocytotic release of monoamine transmitters via reverse transport. Prior studies by us showed that increasing the N-alkyl chain length of N-substituted 4-MA analogues converts 4-MA from a transportable substrate (i.e., releaser) at DAT and NET to a nontransported blocker at these sites. Here, we studied the effects of the individual optical isomers of N-methyl-, N-ethyl-, and N- n-propyl 4-MA on monoamine transporters and abuse-related behavior in rats because action/function might be related to stereochemistry. Uptake inhibition and release assays were conducted in rat brain synaptosomes whereas electrophysiological assessments of drug-transporter interactions were examined using cell-based biosensors. Intracranial-self-stimulation in rats was employed to assess abuse potential in vivo. The experimental evidence demonstrates that S(+) N-methyl 4-MA is a potent and efficacious releaser at DAT, NET, and SERT with the highest abuse potential among the test drugs, whereas R(-) N-methyl 4-MA is a less potent releaser with reduced abuse potential. The S(+)ethyl analogue has decreased efficacy as a releaser at DAT but retains full release activity at NET and SERT with a reduction in abuse-related effects; the R(-)ethyl analogue has a similar profile but is less potent. S(+) N-Propyl 4-MA is a nontransported blocker at DAT and NET but an efficacious releaser at SERT, whereas the R enantiomer is almost inactive. In conclusion, the S enantiomers of the N-alkyl 4-MA analogues are most potent. Lengthening the N-alkyl chain converts compounds from potent nonselective releasers showing abuse-related effects to more selective SERT releasers with no apparent abuse potential.

Lower serotonin transporter binding in patients with cervical dystonia is associated with psychiatric symptoms.

BACKGROUND: Cervical dystonia (CD) is often accompanied by depressive symptoms, anxiety, and jerks/tremor. The dopamine transporter (DAT) binding is related with both depressive symptoms and jerks/tremor in CD. Serotonergic and dopaminergic systems are closely related. As serotonin is involved in the pathophysiology of psychiatric symptoms and jerks, we expected an altered serotoninergic system in CD. We hypothesized that CD is associated with reduced serotonin transporter (SERT) binding, more specific that SERT binding is lower in CD patients with psychiatric symptoms and/or jerks/tremor compared to those without, and to controls. The balance between SERT and DAT binding can be altered in different CD phenotypes. RESULTS: In 23 CD patients and 14 healthy controls, SERT binding in the diencephalon/midbrain was assessed using [123I]FP-CIT SPECT, with a brain-dedicated system. The specific to non-specific binding ratio (binding potential; BPND) to SERT was the main outcome measure. There was a clear trend towards reduced SERT BPND in CD patients with psychiatric symptoms compared to those without (p = 0.05). There was no correlation between SERT binding and dystonia, jerks, or anxiety. There was a significant positive correlation between extrastriatal SERT and striatal DAT BPND in CD patients with jerks, but not in patients without jerks. CONCLUSION: CD patients with psychiatric symptoms have lower SERT binding in the midbrain/diencephalon, while dystonia and jerks appear unrelated to SERT binding. The balance between extrastriatal SERT and striatal DAT binding is different in CD with and without jerks.

A comparative QSAR analysis and molecular docking studies of phenyl piperidine derivatives as potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors.

Depression is a critical mood disorder that affects millions of patients. Available therapeutic antidepressant agents are associated with several undesirable side effects. Recently, it has been shown that Neurokinin 1 receptor (NK1R) antagonists can potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs). In this study, a series of phenyl piperidine derivatives as potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors were applied to quantitative structure-activity relationship (QSAR) analysis. A collection of chemometrics methods such as multiple linear regression (MLR), factor analysis-based multiple linear regression (FA-MLR), principal component regression (PCR), and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were applied to make relations between structural characteristics and NK1R antagonism/SERT inhibitory of these compounds. The best multiple linear regression equation was obtained from GA-PLS and MLR for NK1R and SERT, respectively. Based on the resulted model, an in silico-screening study was also conducted and new potent lead compounds based on new structural patterns were designed for both targets. Molecular docking studies of these compounds on both targets were also conducted and encouraging results were acquired. There was a good correlation between QSAR and docking results. The results obtained from validated docking studies indicate that the important amino acids inside the active site of the cavity that are responsible for essential interactions are Glu33, Asp395 and Arg26 for SERT and Ala30, Lys7, Asp31, Phe5 and Tyr82 for NK1R receptors.

Fluoxetine and its active metabolite norfluoxetine disrupt estrogen synthesis in a co-culture model of the feto-placental unit.

The effects of fluoxetine, one of the most prescribed selective serotonin-reuptake inhibitors (SSRIs) during pregnancy, and its active metabolite norfluoxetine were studied on placental aromatase (CYP19) and feto-placental steroidogenesis. Fluoxetine did not alter estrogen secretion in co-culture of fetal-like adrenocortical (H295R) and trophoblast-like (BeWo) cells used as a model of the feto-placental unit, although it induced CYP19 activity, apparently mediated by the serotonin (5-HT)2A receptor/PKC signaling pathway. Norfluoxetine decreased estrogen secretion in the feto-placental co-culture and competitively inhibited catalytic CYP19 activity in BeWo cells. Decreased serotonin transporter (SERT) activity in the co-culture was comparable to 17ß-estradiol treatment of BeWo cells. This work shows that the complex interaction of fluoxetine and norfluoxetine with placental estrogen production, involves 5-HT-dependent and -independent mechanisms. Considering the crucial role of estrogens during pregnancy, our results raise concern about the impact of SSRI treatment on placental function and fetal health.

Spatiotemporal SERT expression in cortical map development.

The cerebral cortex is organized into morphologically distinct areas that provide biological frameworks underlying perception, cognition, and behavior. Profiling mouse and human cortical transcriptomes have revealed temporal-specific differential gene expression modules in distinct neocortical areas during cortical map establishment. However, the biological roles of spatiotemporal gene expression in cortical patterning and how cortical topographic gene expression is regulated are largely unknown. Here, we characterize temporal- and spatial-defined expression of serotonin (5-HT) transporter (SERT) in glutamatergic neurons during sensory map development in mice. SERT is transiently expressed in glutamatergic thalamic neurons projecting to sensory cortices and in pyramidal neurons in the prefrontal cortex (PFC) and hippocampus (HPC) during the period that lays down the basic functional neural circuits. We previously identified that knockout of SERT in the thalamic neurons blocks 5-HT uptake by their thalamocortical axons, resulting in excessive 5-HT signaling that impairs sensory map architecture. In contrast, here we show that selective SERT knockout in the PFC and HPC neurons does not perturb sensory map patterning. These data suggest that transient SERT expression in specific glutamatergic neurons provides area-specific instructions for cortical map patterning. Hence, genetic and pharmacological manipulations of this SERT function could illuminate the fundamental genetic programming of cortex-specific maps and biological roles of temporal-specific cortical topographic gene expression in normal development and mental disorders.

Association between the serotonin transporter and cytokines: Implications for the pathophysiology of bipolar disorder.

BACKGROUND: Reduced brain serotonin transporter (SERT) has been demonstrated in bipolar disorder (BD). The aim of this study was to explore the potential role of cytokines on reduced SERT in BD. METHODS: Twenty-eight BD type I patients and 28 age- and gender-matched healthy controls (HCs) were recruited. Single photon emission computed tomography with the radiotracer 123I ADAM was used for SERT imaging. Regions of interest included the midbrain, thalamus, putamen and caudate. Seven cytokines, including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1α (IL-1α), IL-1ß, IL-4, IL-6 and IL-10, were measured using an enzyme linked immune-sorbent assay. RESULTS: SERT availability in the midbrain and caudate was significantly lower in BD compared to HCs. IL-1ß was significantly lower, whereas IL-10 was significantly higher in BD compared to HCs. Multiple linear regression analyses revealed that there were associations between cytokines, IL-1α, IL-1ß, IL-6 and SERT availability in the midbrain but not in the thalamus, putamen and caudate. Furthermore, linear mixed effect analyses demonstrated that these associations were not different between HCs and BD. CONCLUSION: While many cytokines have been proposed to be important in the pathophysiology of BD, our results demonstrated that significant associations between cytokines and SERT availability may explain the role of cytokines in mood regulation. However, these associations were not different between HCs and BD, which imply the role of these cytokines is not specific for BD.

Neither cortisol nor brain-derived neurotrophic factor is associated with serotonin transporter in bipolar disorder.

Converging evidence indicates the hypothalamus-pituitary-adrenal axis and serotonergic neurons exert reciprocal modulatory actions. Likewise, brain-derived neurotrophic factor (BDNF) has been implicated as a growth and differentiation factor in the development of serotonergic neurons. The aim of this study was to examine the interaction of cortisol and BDNF on serotonin transporter (SERT) in bipolar disorder (BD). Twenty-eight BD and 28 age- and gender-matched healthy controls (HCs) were recruited. (123)I-ADAM with single-photon emission computed tomography (SPECT) was applied for measurement of SERT availability in the brain, which included the midbrain, thalamus, putamen and caudate. Ten milliliters of venous blood was withdrawn, when the subject underwent SPECT, for the measurement of the plasma concentration of cortisol and BDNF. SERT availability was significantly decreased in the midbrain and caudate of BD compared with HCs, whereas plasma concentration of cortisol and BDNF did not show a significant difference. The linear mixed-effect model revealed that there was a significant interaction of group and cortisol on SERT availability of the midbrain, but not BDNF. Linear regression analyses by groups revealed that cortisol was associated with SERT availability in the midbrain in the HCs, but not in BD. Considering previous studies, which showed a significant association of cortisol with SERT availability in the HCs and major depressive disorder (MDD), our result replicated a similar finding in HCs. However, the negative finding of the association of cortisol and SERT availability in BD, which was different from MDD, suggests a different role for cortisol in the pathophysiology of mood disorder.

Gpm6b deficiency impairs sensorimotor gating and modulates the behavioral response to a 5-HT2A/C receptor agonist.

The neuronal tetraspan proteins, M6A (Gpm6a) and M6B (Gpm6b), belong to the family of proteolipids that are widely expressed in the brain. We recently reported Gpm6a deficiency as a monogenetic cause of claustrophobia in mice. Its homolog proteolipid, Gpm6b, is ubiquitously expressed in neurons and oligodendrocytes. Gpm6b is involved in neuronal differentiation and myelination. It interacts with the N-terminal domain of the serotonin transporter (SERT) and decreases cell-surface expression of SERT. In the present study, we employed Gpm6b null mutant mice (Gpm6b(-/-)) to search for behavioral functions of Gpm6b. We studied male and female Gpm6b(-/-) mice and their wild-type (WT, Gpm6b(+/+)) littermates in an extensive behavioral test battery. Additionally, we investigated whether Gpm6b(-/-) mice exhibit changes in the behavioral response to a 5-HT2A/C receptor agonist. We found that Gpm6b(-/-) mice display completely normal sensory and motor functions, cognition, as well as social and emotionality-like (anxiety, depression) behaviors. On top of this inconspicuous behavioral profile, Gpm6b(-/-) mice of both genders exhibit a selective impairment in prepulse inhibition of the acoustic startle response. Furthermore, in contrast to WT mice that show the typical locomotion suppression and increase in grooming activity after intraperitoneal administration of DOI [(±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride], Gpm6b(-/-) mice demonstrate a blunted behavioral response to this 5-HT2A/C receptor agonist. To conclude, Gpm6b deficiency impairs sensorimotor gating and modulates the behavioral response to a serotonergic challenge.

Asymmetric effects of low doses of progesterone on GABA(A) receptor α4 subunit protein expression in the olfactory bulb of female rats.

The aim of this study was to evaluate the effect of progesterone on the protein expression of α4 subunit of GABA(A) receptor, serotonin transporter (SERT), Akt, Erk, and caspase-3 in the olfactory bulb (OB) of female rats exposed to the forced swimming test (FST). Female rats were injected daily with progesterone (0.4 mg/kg body mass) or vehicle during 2 complete oestrous cycles and exposed to the FST, and the protein expression of GABA(A) receptor α4 subunit, SERT, Akt, Erk, and caspase-3 in the OB were evaluated. Progesterone increased the expression of the α4 subunit in the right OB and decreased its expression in the left OB, although it did not change the expression of other proteins. In summary, our findings indicate that progesterone has an asymmetric modulatory effect on the expression of GABA(A) receptor α4 subunit in the OB. This effect could be related to the antidepressant-like effect of progesterone in female rats.