Murphy DL, Lesch KP. Targeting the murine serotonin transporter: insights into human neurobiology. Nat Rev Neurosci 9: 85-96

Laboratory of Clinical Science, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature Reviews Neuroscience (Impact Factor: 31.43). 03/2008; 9(2):85-96. DOI: 10.1038/nrn2284
Source: PubMed


Mutations resulting in reduced or completely abrogated serotonin-transporter (SERT) function in mice have led to the identification of more than 50 different phenotypic changes, ranging from increased anxiety and stress-related behaviours to gut dysfunction, bone weakness and late-onset obesity with metabolic syndrome. These multiple effects, which can be amplified by gene-environment and gene-gene interactions, are primarily attributable to altered intracellular and extracellular serotonin concentrations during development and adulthood. Much of the human data relating to altered expression of the gene that encodes SERT are based on genetic-association findings or correlations and are therefore not as robust as the experimental mouse results. Nevertheless, SERT-function-modifying gene variants in humans apparently produce many phenotypes that are similar to those that manifest themselves in mice.

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    • "For instance 5-HT blood level, which is the first biomarker to be identified in individuals with ASD, is found elevated in more than 25% of autistic patients (Gabriele et al., 2014). Given that 5-HT plays a crucial role in the regulation of behavioral, autonomic and cognitive functions, it is not surprising that its level is found altered in patients with ASD (Murphy and Lesch, 2008). Other biochemical markers of interest for the diagnosis of ASD are urinary solutes that mostly consist of tryptophan and nicotinic metabolites (Yap et al., 2010). "
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    ABSTRACT: Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders that is among the most severe in terms of prevalence, morbidity and impact to the society. It is characterized by complex behavioral phenotype and deficits in both social and cognitive functions. Although the exact cause of ASD is still not known, the main findings emphasize the role of genetic and environmental factors in the development of autistic behavior. Environmental factors are also likely to interact with the genetic profile and cause aberrant changes in brain growth, neuronal development, and functional connectivity. The past few years have seen an increase in the prevalence of ASD, as a result of enhanced clinical tests and diagnostic tools. Despite growing evidence for the involvement of endogenous biomarkers in the pathophysiology of ASD, early detection of this disorder remains a big challenge. This paper describes the main behavioral and cognitive features of ASD, as well as the symptoms that differentiate autism from other developmental disorders. An attempt will be made to integrate all the available evidence which point to reduced brain connectivity, mirror neurons deficits, and inhibition-excitation imbalance in individuals with ASD. Finally, this review discusses the main factors involved in the pathophysiology of ASD, and illustrates some of the most important markers used for the diagnosis of this debilitating disorder. Copyright © 2015. Published by Elsevier Ltd.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 04/2015; 43. DOI:10.1016/j.ijdevneu.2015.04.003 · 2.58 Impact Factor
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    • "Therefore, it may be proposed that 5-HT in the cytosol of cardiomyocytes modifies the contractile proteins (actin and myosin), thus participating in the autocrine and paracrine modulation of the heart muscular tone. A key protein involved in the removal of plasma 5-HT is SERT and it is responsible for bioamine internalization (Levy, 2006; Pavone et al., 2007; Murphy and Lesch, 2008). It has been reported that SERT is expressed in cardiomyocytes during fetal life (Nebigil et al., 2000; Sari and Zhou, 2003; Pavone et al., 2007) and has been demonstrated only in endocardium and endothelium of the coronary and capillary arteries, suggesting that these cells have a high capacity for uptake of the circulating 5- HT for its degradation (Mekontso et al., 2006; Pavone et al., 2007). "
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    ABSTRACT: The objective of this study was to characterize biochemically and immunohistochemically an intrinsic serotonergic system in rat heart. Male Wistar rats were used with an average body weight of 250 ± 10 g. Rats were adapted for 2 weeks to standard animal laboratory conditions. Hearts were later obtained to determine the principal components of the serotoninergic system using immunohistochemistry and Western blot for tryptophan-5-hydroxylase (TPH) 1 or 2, serotonin transporter (SERT) and serotoninergic receptors 5-HT 1B , 5-HT 2A , 5-HT 2B and 5-HT 4. Activity of TPH, L-tryptophan (L-Trp), 5-hydroxytryptamine (serotonin, 5-HT) and 5-hydroxyindolacetic acid (5-HIAA) were also determined by high-resolution liquid chromatography. Immunopositive cardiomyocytes for both isoforms of TPH were observed. There was a greater expression of TPH2in relation to TPH1. Immunoreactivity for SERT and 5-HT 1B , 5-HT 2A , 5-HT 2B and 5-HT 4 receptors was also observed in cardiomyocytes. TPH activity, L-Trp, 5-HT and 5-HIAA concentrations were also demonstrated in heart tissue.These findings support the fact that cardiomyocytes synthesize, utilize and reuptake 5-HT, which constitutes an intrinsic serotoninergic system that actively participates as an autocrine and paracrine modulation system of heart activities.
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    • "5-HTTOE mice have approximately threefold greater SERT expression than their wild-type (WT) counterparts , as verified by radioligand binding of [ 3 H]-citalopram (Jennings et al. 2006; Barkus et al. 2014). This difference mirrors the range of natural 5-HTT variation in humans (Lundberg et al. 2007), and is comparable to the proposed difference between the L A /L A and SS genotypes (Murphy & Lesch 2008). 5-HTTOE mice therefore provide a more physiologically relevant model of variation in human 5-HTT expression when compared to 5-HTT knock-out rodents, for example, because humans do not exhibit a complete loss of 5-HTT expression. "
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    ABSTRACT: The long allele variant of the serotonin transporter (SERT, 5-HTT) gene-linked polymorphic region (5-HTTLPR) is associated with higher levels of 5-HTT expression and reduced risk of developing affective disorders. However, little is known about the mechanisms underlying this protective effect. One hypothesis is that 5-HTT expression influences aversive information processing, with reduced negative cognitive bias present in those with higher 5-HTT expression. Here we investigated this hypothesis using genetically-modified mice and a novel aversive learning paradigm. Mice with high levels of 5-HTT expression (5-HTT over-expressing, 5-HTTOE mice) and wild-type mice were trained to discriminate between three distinct auditory cues: one cue predicted footshock on all trials (CS+); a second cue predicted the absence of footshock (CS-); and a third cue predicted footshock on 20% of trials (CS20%), and was therefore ambiguous. Wild-type mice exhibited equivalently high levels of fear to the CS+ and CS20% and minimal fear to the CS-. In contrast, 5-HTTOE mice exhibited high levels of fear to the CS+ but minimal fear to the CS- and the CS20%. This selective reduction in fear to ambiguous aversive cues suggests that increased 5-HTT expression reduces negative cognitive bias for stimuli with uncertain outcomes. This article is protected by copyright. All rights reserved.
    Genes Brain and Behavior 03/2015; 14(4). DOI:10.1111/gbb.12215 · 3.66 Impact Factor
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