Serotonin Transporter Deficiency Induces Metabolic Alterations in the Ileal Mucosa
Nathan CalzadillaDulari JayawardenaAisha QaziAnchal SharmaKai MonganShane ComiskeyAbhijith EatharaSeema SaksenaPradeep K. DudejaWaddah A. AlrefaiRavinder K. Gill
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Serotonin transporter (SERT) deficiency has been implicated in metabolic syndrome, intestinal inflammation, and microbial dysbiosis. Interestingly, changes in microbiome metabolic capacity and several alterations in host gene expression, including lipid metabolism, were previously observed in SERTKeywords:
Intestinal mucosa
Serotonin uptake, mediated by the serotonin transporter (SERT), is blocked acutely by antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), but such blockade does not correlate temporally with the onset of therapeutic improvement. Treatment with SSRIs for 21 d induced downregulation of the SERT (Benmansour et al., 1999). The time course of SERT downregulation as well as the time course for its recovery after cessation of treatment with the SSRI sertraline were investigated using tritiated cyanoimipramine to measure SERT binding sites. To determine if there was a temporal correlation between the time when sertraline induced downregulation of the SERT and when marked alteration in SERT function occurred, clearance of locally applied 5-HT into the CA3 region of hippocampus was achieved using in vivo electrochemistry. After 4 or 10 d treatment with sertraline, SERT binding sites decreased very little (15–30%), and the chronoamperometric signals for serotonin in sertraline-treated rats were comparable with ones obtained in control animals. By contrast, after 15 d of treatment, when SERT binding sites were markedly reduced by 80%, there was robust decrease in the clearance of 5-HT. Moreover, the functional consequences of SERT downregulation as measured by chronoamperometry were significantly greater than those seen after acute blockade of the SERT by SSRIs. SERT binding sites decreases are not a consequence of reduced SERT gene expression, as revealed by in situhybridization measurements. SSRI-induced downregulation of the SERT may be a key component for the clinical response to SSRIs.
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Back to table of contents Previous article Next article Clinical & Research NewsFull AccessOCD Patients Stalked By Mutant GeneJim RosackJim RosackSearch for more papers by this authorPublished Online:21 Nov 2003https://doi.org/10.1176/pn.38.22.0026Researchers at the National Institute of Mental Health (NIMH) have discovered a rare combination of two mutations within one gene that codes the serotonin transporter that together appear to lead to treatment-resistant obsessive-compulsive disorder (OCD).The report may be the first in which two mutations within the same gene contribute to a psychiatric disorder.The hSERT gene codes for the human serotonin transporter—the membrane protein responsible for the reuptake of serotonin from the synapse between two neurons. It is the transporter protein that is bound by serotonin reuptake inhibitors (SSRIs), resulting in blocking the transporter’s function and leaving more serotonin available for neuronal communication within the synapse.The researchers at NIMH, along with Japanese collaborators, discovered a mutation within the hSERT gene, which they labeled I425V. The mutation appears to be associated with an increased expression of the hSERT gene, resulting in more transporter proteins appearing in the neuron’s membrane. This results in increased reuptake of serotonin in those neuronal synapses, decreasing the amount of serotonin available in the synapse for signaling.The second mutation identified, a long allele of the promoter portion of the serotonin transporter gene (5-HTTLPR), results in similar cellular effects—an increase in transporter proteins leading to less serotonin being available for neuronal communication.The two mutations appearing together result in a significantly lower amount of serotonin available within the synapse than is seen with either one of the mutations alone.The research, funded by NIMH, was reported in the October 23 issue of Molecular Psychiatry.A Double Hit“In all of molecular medicine, there are few known instances where two variants within one gene have been found to alter the expression and regulation of the gene in a way that appears associated with symptoms of a disorder,” co-author Dennis Murphy, M.D., a researcher in the NIMH Laboratory of Clinical Science, said in a prepared statement. “This step forward gives us a glimpse of the complications ahead in studying the genetic complexity of neuropsychiatric disorders.”Murphy and his colleagues studied the DNA of 170 unrelated individuals, including 30 with OCD, 30 with eating disorders, and 30 with seasonal affective disorder. The remainder served as healthy control subjects. Two patients with OCD were found to have the first mutation, I425V. The mutation did not appear in any other patients or control subjects.Family Interviews ConductedIn addition, psychiatric interviews were completed with each patient’s families, revealing that five relatives of the two patients with the I425V mutation had histories of OCD or obsessive-compulsive personality disorder. Some also had anorexia nervosa, Asperger’s syndrome, social phobia, or a substance abuse disorder.Further DNA analysis revealed that the two patients with OCD who carried the I425V mutation, as well as their two siblings, also had the second mutation in the hSERT gene—the 5-HTTLPR mutation. “This variant, associated with an increased expression and function of the serotonin transporter, suggests a double hit, or two changes within the same gene,” the authors noted.The combination of the two mutations could account for the “unusual severity and treatment resistance of the illnesses in the subjects and their siblings.”NIMH Director Thomas Insel, M.D., said, “This is a new model for neuropsychiatric genetics—the concept of two or more within-gene modifications being important in each affected individual. This is probably the first report of a modification in a transporter gene resulting in a gain rather than a decrease in [its] function.”An abstract of the article is posted on the Web at www.nature.com/mp/journal/v8/n10/index.html. ▪ ISSUES NewArchived
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Earlier platelet and postmortem brain studies have found alterations in serotonin transporter function in ethanol-abusing human subjects. The present investigation tested the hypothesis that brain serotonin transporter function is altered in chronic users of ethanol and cocaine, which might be related to a common serotonin transporter promoter polymorphism.Serotonin transporter binding sites, serotonin transporter mRNA levels, and serotonin transporter promoter variants were quantified in postmortem samples from a group of human subjects who had been ethanol users or cocaine users and then compared to those of a matched group of comparison subjects. Quantitative autoradiographic and in situ hybridization assays were performed in midbrain samples that contained the dorsal and median raphe nuclei (the location of serotonin cell bodies that innervate the forebrain).There was a significant overall cocaine-by-ethanol-by-genotype interaction. Dorsal raphe [125I]CIT binding to the serotonin transporter was lower in cocaine users than in comparison subjects. In addition, serotonin transporter binding and serotonin transporter mRNA levels varied significantly by genotype. It was also found that serotonin transporter binding in subjects with either the short or heterozygote genotype was significantly higher in the ethanol-user subjects.Serotonin transporter binding sites were regulated in a region-specific and substance-specific pattern, which was not simply a local response to functional blockade. Also, a reciprocal relationship appeared to exist between cocaine and ethanol effects in the dorsal raphe, which may have interesting clinical implications for dual-diagnosis patients. It is possible that serotonin transporter promoter genotype may play a complex role in chronic ethanol dependence.
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Serotonin uptake, mediated by the serotonin transporter (SERT), is blocked acutely by antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), but such blockade does not correlate temporally with the onset of therapeutic improvement. Treatment with SSRIs for 21 d induced downregulation of the SERT (Benmansour et al., 1999). The time course of SERT downregulation as well as the time course for its recovery after cessation of treatment with the SSRI sertraline were investigated using tritiated cyanoimipramine to measure SERT binding sites. To determine if there was a temporal correlation between the time when sertraline induced downregulation of the SERT and when marked alteration in SERT function occurred, clearance of locally applied 5-HT into the CA3 region of hippocampus was achieved using in vivo electrochemistry. After 4 or 10 d treatment with sertraline, SERT binding sites decreased very little (15-30%), and the chronoamperometric signals for serotonin in sertraline-treated rats were comparable with ones obtained in control animals. By contrast, after 15 d of treatment, when SERT binding sites were markedly reduced by 80%, there was robust decrease in the clearance of 5-HT. Moreover, the functional consequences of SERT downregulation as measured by chronoamperometry were significantly greater than those seen after acute blockade of the SERT by SSRIs. SERT binding sites decreases are not a consequence of reduced SERT gene expression, as revealed by in situ hybridization measurements. SSRI-induced downregulation of the SERT may be a key component for the clinical response to SSRIs.
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RNA editing is a post-transcriptional process, which has the potential to alter the function of encoded proteins. In particular, serotonin 2C receptor (5-HT2cR) mRNA editing can produce 24 protein isoforms of varying functionality. Rodent studies have shown that 5-HT2cR editing is dynamically modulated in response to environmental challenges. Basal extracellular serotonin, which is strongly influenced by serotonin transporter (SERT), was proposed as a potential trigger for this modulation; however, the data remain inconclusive. Here, 5-HT2cR editing is evaluated in SERT mutant versus wild-type rats, and in humans with different SERT genotypes. Our findings argue against the hypothesis that 5-HT2cR editing efficiency is regulated by extracellular serotonin levels.
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Obsessive compulsive disorder (OCD) is a neuropsychiatric condition that has been shown to be heritable and for which a major gene effect has been reported based on segregation studies1,2. However, linkage analysis studies have not been able to confirm a locus for OCD3. The most promising candidate genes for OCD at the present time are in the serotonin system and the glutamate system4. The SCL6A4 gene has been the most extensively studied functional polymorphism in psychiatry, providing worldwide evidence of its importance in several disorders, such as OCD.
The efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of OCD has lead to the hypothesis of a serotonergic dysfunction in this disorder5. Since SSRIs acts on the serotonin (5HT) transporter (5HTT), it has been suggested that the 5HTT gene (SCL6A4), located on chromosome 17q126, could be a good candidate for OCD7–9. A functional polymorphism in the promoter region has been described10. This 5HTT-linked polymorphic region (5HTTLPR) is situated in a GC-rich region composed of 20-23 bp repeat units. The biallelic polymorphism consists of an insertion (long allele, “1”) or a deletion (short allele, “s”) of 44 bp. The serotonin transporter (SERT) is probably the most widely studied gene in psychiatry11. Previous studies have reported the “l” allele is as characterized by increased transcriptional activity as well as increased basal re-uptake of 5-HT in vitro compared with the short form of the 5HTTLPR10.
A possible association between 5HTTLPR polymorphism and OCD has been studied by some research groups. Billett et al7 could not find an association in 72 OCD patients compared to 72 controls. However, a relative increase (not statistically significant) of homozygous (“l” allele) in the OCD group was observed. Bengel et al8, reported that OCD patients were more likely to carry two copies of the long allele (“l”), compared to controls. A study by McDougle et al9 using a family-controlled transmission disequilibrium test (TDT), reported a predominant “l” allele transmission in 24 heterozygous parents to their OCD affected sibs. A preferred “l” allele transmission was also observed in 10 out of 13 SSRI non-responders. In addition, an analysis of SCL6A4 coding region has not revealed differences in OCD patients12. As suggested by these studies of a possible relationship between OCD and the “l” allele, our group analyzed the 5-HTTLPR polymorphism in Mexican OCD patients using a case-control methodology. Besides, we analyzed alternative methods that employ family-based sampling to minimize the effects of population heterogeneity in a sample of 43 trios13. Our results did not show a positive association between this variant and Mexican OCD patients. However, previous studies showed an association between OCD and “l” allele of 5-HTTLPR polymorphism, although the literature still remains controversial8,13–15. In the case of Hu et al14, a single nucleotide polymorphism (SNP) that converts the long allele to a functionally short one was important in determining the significance of the SERT gene in OCD. The long allele containing the A variant of the SNP was associated with OCD, while the long-G and short alleles were not. Thus other groups should investigate this SNP in their analyses.
In addition, many association studies have resulted in controversial results because population stratification cannot easily be avoided16. Later studies showed that allele frequencies of the 5HTTLPR could vary widely between populations. The allele frequencies of our control group13 were similar to Caucasian and European-American populations previously reported8,17. These frequencies differ from those reported for Japanese and African-American subjects18. Since use of family-based approaches like TDT and HHRR may overcome ethnic stratification, analyzing a sample of trios for confirmation of an association between OCD and the SCL6A4 gene should always be performed. Family-based association analysis confirmed negative linkage disequilibrium between the 5HTTLPR polymorphism and OCD. TDT and HRR analysis did not reveal preferential “l” allele transmission. These studies did not support McDougle’s initial hypothesis9that the “s” allele would be associated with increased susceptibility to OCD. This hypothesis was based on the report of an association between the “s” allele and neuroticism17and confirmed later in the susceptibility to depression in interaction with life events19. Neuroticism shares common genetic origins with affective and anxiety disorders, with each of many genes thought to contribute small amounts of variance20. Also, an association between 5HTTLPR and some disorders such as depression, life events and depression in psychosis and seasonal affective disorder and seasonality has been observed21–24. All these findings, relating the “s” allele with some psychiatric disorders, may agree with the 5HT-anxiogenic theory and with the SSRI mechanism of action in these disorders as proposed by Lesch et al17. Moreover, if the expression of 5HTT is reduced in carriers of the “s” allele, the same dose of SSRI could increase synaptic 5-HT and induce desensitization of several postsynaptic 5-HT receptors. Since the evidence may support the hypothesis of a relationship between the “s” allele and anxiety-related personality traits, studies of phenotypes based on personality traits in OCD combined with the analysis of 5HTTLPR polymorphism may provide an important tool in disentangling genetic factors involved in the disorder. Extensive family-based studies combined with population genetic studies are needed, from large, and carefully collected samples using various phenotype definitions such as co-morbidity, age of onset, type of obsessions and compulsions, and personality an temperament dimensions among others before reaching a more definitive conclusion.
New evidence showing that some of the previous results may differ since the involvement of the 5HTTLPR (A/G) gene polymorphism modulating the 5HTTLPR, it may impose to new studies the need to assess this polymorphism. In addition, most association data come from case-control studies that do not assess population stratification instead of family based samples. The study presented in this issue by Tibrewal et al25, addresses both methodological concerns. It evaluates population stratification as well as the modulating 5HTTLPR (A/G) gene polymorphism. Due to small sample size it is difficult to see an effect of common genes of minor effects. Probably, some of the rare gene variants (CNVs) in these common alleles may have a larger effect in disease aetiology. However, it is intriguing to find a modest statistically significant association of the dominant model of 5HTTLPR (A/G) (non-risk allele: LA; risk alleles: SA, SG, LG) with the severity index or YBOCS score. These data may support the idea that the 5-HT system is altered in the brain of OCD patients depending upon severity. This sub-sample (including the ethnic component) may provide a great opportunity to further explore the contribution of rare variants by methods of deep sequencing. If the peripheral findings translate into the brain, increased 5-HT uptake or storage in the presynaptic terminal would be expected to diminish extracellular 5-HT availability. Unfortunately, a direct assessment of synaptic 5-HT in patients with OCD is not possible with present technologies. However, clinical pharmacological data may also provide additional phenotypes to better understand the participation of 5-HT in OCD genetic risk.
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The serotonin transporter (SERT) is a neuronal plasma membrane protein whose primary function is to take up the neurotransmitter serotonin from the extracellular space, thereby controlling the spatial and temporal aspects of serotonergic signaling in the brain. In humans, a commonly expressed genetic variant of the serotonin transporter gene results in 40% reductions in SERT expression that have been linked to increases in anxiety-related personality traits and susceptibility to stress-associated depression. Mice have been engineered to express similar reductions in SERT expression to investigate transporter-mediated control of serotonin neurotransmission and behavior. We employed carbon fiber microelectrode voltammetry (chronoamperometry) to examine serotonin clearance rates in brain liposomes (synaptosomes) prepared from mice with 50% (SERT+/-) or complete (SERT-/-) loss of SERT expression. Initial characterization of uptake showed that transport of serotonin was enhanced in the presence of oxygen and abolished when synaptosomes were stirred. Additionally, uptake was prevented by inclusion of the serotonin-selective reuptake inhibiting drug paroxetine in the incubation medium. Most notably, unlike prior studies using established radiochemical methods in synaptosomes, we determined 60% reductions in serotonin uptake rates in SERT+/- mice in two different brain regionsstriatum and frontal cortex. Serotonin uptake was not detected in either brain region in SERT-/- mice. Thus, electroanalytical methods offer distinct advantages stemming from excellent temporal resolution for determining transporter kinetics. Moreover, these appear necessary for delineating moderate but biologically important changes in neurotransmitter transporter function.
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The highly evolutionarily conserved serotonin transporter (SERT) regulates the entire serotoninergic system and its receptors via modulation of extracellular fluid serotonin concentrations. Differences in SERT expression and function produced by three SERT genes and their variants show associations with multiple human disorders. Screens of DNA from patients with autism, ADHD, bipolar disorder, and Tourette's syndrome have detected signals in the chromosome 17q region where SERT is located. Parallel investigations of SERT knockout mice have uncovered multiple phenotypes that identify SERT as a candidate gene for additional human disorders ranging from irritable bowel syndrome to obesity. Replicated studies have demonstrated that the SERT 5'-flanking region polymorphism SS genotype is associated with poorer therapeutic responses and more frequent serious side effects during treatment with antidepressant SERT antagonists, namely, the serotonin reuptake inhibitors (SRIs).
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