Molecular Genetics of the Platelet Serotonin System in First-Degree Relatives of Patients with Autism

Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 02/2008; 33(2):353-60. DOI: 10.1038/sj.npp.1301406
Source: PubMed


Elevated platelet serotonin (5-hydroxytryptamine, 5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood 5-HT, 5-HT binding affinity for the serotonin transporter (K(m)), 5-HT uptake (V(max)), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in 24 first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. All subjects were then genotyped for selected polymorphisms at the SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 loci. Previous studies allowed an a priori prediction of SLC6A4 haplotypes that separated the subjects into three groups that showed significantly different 5-HT binding affinity (K(m), p=0.005) and 5-HT uptake rate (V(max), p=0.046). Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT. Haplotype analysis of two polymorphisms in TPH1 revealed a nominally significant association with whole blood 5-HT (p=0.046). These initial studies of indices of the 5-HT system with several single-nucleotide polymorphisms at loci in this system generate hypotheses for testing in other samples.

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    • "Blood 5-HT levels are utilized as an endophenotype for neuropsychiatric disorders in humans (DeLisi et al, 1981; Cook and Leventhal, 1996; Cleare, 1997; Askenazy et al, 1998; Verkes et al, 1998; Ma et al, 2007; Wulsin et al, 2009). The ITGB3 gene, coding for the integrin β3 subunit, has been consistently identified as a quantitative locus for regulating whole blood 5-HT levels (Weiss et al, 2004, 2006a; Coutinho et al, 2007; Cross et al, 2008). The platelet integrin αIIbβ3 receptor (also known as glycoprotein IIb/IIIa) was discovered to directly interact with SERT and modulate SERTmediated uptake of extracellular 5-HT (Carneiro et al, 2008). "
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    ABSTRACT: Converging lines of evidence have identified genetic interactions between the SERT gene and ITGB3, which encodes the β3 subunit that forms the αIIbβ3 and αvβ3 integrin receptor complexes. Here, we examine the consequences of haploinsufficiency in the mouse integrin β3 subunit gene (Itgb3) on SERT function and selective 5-HT reuptake inhibitor (SSRI) effectiveness in vivo. Biochemical fractionation studies and immunofluorescent staining of murine brain slices reveal that αvβ3 receptors and SERT are enriched in presynaptic membranes from several brain regions and that αvβ3 colocalizes with a subpopulation of SERT-containing synapses in raphe nuclei. Notably, we establish that loss of a single allele of Itgb3 in murine neurons is sufficient to decrease 5-HT uptake by SERT in midbrain synaptosomes. Pharmacological assays to elucidate the αvβ3-mediated mechanism of reduced SERT function indicate that decreased integrin β3 subunit expression scales down the population size of active SERT molecules and, as a consequence, lowers the effective dose of SSRIs. These data are consistent with the existence of a subpopulation of SERTs that are tightly modulated by integrin αvβ3 and significantly contribute to global SERT function at 5-HT synapses in the midbrain. Importantly, our screen of a normal human population for single nucleotide polymorphisms in human ITGB3 identified a variant associated with reductions in integrin β3 expression levels that parallel our mouse findings. Thus, polymorphisms in human ITGB3 may contribute to the differential responsiveness of select patients to SSRIs.Neuropsychopharmacology accepted article preview online, 16 February 2015. doi:10.1038/npp.2015.51.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2015; 40(8). DOI:10.1038/npp.2015.51 · 7.05 Impact Factor
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    • "The gene coding for the 5-HTT, named SLC6A4, exists in various alleles related to different degrees of 5-HTT expression and/or activity. Polymorphism of the SLC6A4 gene has been correlated with autism, although results from different groups are heterogeneous with respect to the polymorphic sites involved and the type of allele associated with autism (Devlin et al., 2005; Cho et al., 2007; Coutinho et al., 2007; Wassink et al., 2007; Cross et al., 2008); however, others did not find any significant association (Ramoz et al., 2006). A SLC6A4 variant coding for an overactive form of 5-HTT has been identified in families of autistic patients (Sutcliffe et al., 2005). "
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    ABSTRACT: Serotonin type 7 receptors (5-HT7) are expressed in several brain areas, regulate brain development, synaptic transmission and plasticity, and therefore are involved in various brain functions such as learning and memory. A number of studies suggest that 5-HT7 receptors could be potential pharmacotherapeutic target for cognitive disorders. Several abnormalities of serotonergic system have been described in patients with autism spectrum disorder (ASD), including abnormal activity of 5-HT transporter, altered blood and brain 5-HT levels, reduced 5-HT synthesis and altered expression of 5-HT receptors in the brain. A specific role for 5-HT7 receptors in ASD has not yet been demonstrated but some evidence implicates their possible involvement. We have recently shown that 5-HT7 receptor activation rescues hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome, a monogenic cause of autism. Several other studies have shown that 5-HT7 receptors modulate behavioral flexibility, exploratory behavior, mood disorders and epilepsy, which include core and co-morbid symptoms of ASD. These findings further suggest an involvement of 5-HT7 receptors in ASD. Here, we review the physiological roles of 5-HT7 receptors and their implications in Fragile X Syndrome and other ASD.
    Frontiers in Cellular Neuroscience 08/2014; 8:250. DOI:10.3389/fncel.2014.00250 · 4.29 Impact Factor
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    • "Many studies on the pathophysiological mechanisms of autism have focused on the serotonergic system. Prior studies have consistently found elevated serotonin levels in the whole blood cells and platelets of autism patients [1-5] and their relatives [6-8]. Short-term dietary depletion of tryptophan (the precursor of serotonin) has been shown to exacerbate repetitive behavior and to elevate anxiety and feelings of unhappiness in autistic adults [9]. "
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    ABSTRACT: Changes in serotonin transporter (SERT) function have been implicated in autism. SERT function is influenced by the number of transporter molecules present at the cell surface, which is regulated by various cellular mechanisms including interactions with other proteins. Thus, we searched for novel SERT-binding proteins and investigated whether the expression of one such protein was affected in subjects with autism. Novel SERT-binding proteins were examined by a pull-down system. Alterations of SERT function and membrane expression upon knockdown of the novel SERT-binding protein were studied in HEK293-hSERT cells. Endogenous interaction of SERT with the protein was evaluated in mouse brains. Alterations in the mRNA expression of SERT (SLC6A4) and the SERT-binding protein in the post-mortem brains and the lymphocytes of autism patients were compared to nonclinical controls. N-ethylmaleimide-sensitive factor (NSF) was identified as a novel SERT-binding protein. NSF was co-localized with SERT at the plasma membrane, and NSF knockdown resulted in decreased SERT expression at the cell membranes and decreased SERT uptake function. NSF was endogenously co-localized with SERT and interacted with SERT. While SLC6A4 expression was not significantly changed, NSF expression tended to be reduced in post-mortem brains, and was significantly reduced in lymphocytes of autistic subjects, which correlated with the severity of the clinical symptoms. These data clearly show that NSF interacts with SERT under physiological conditions and is required for SERT membrane trafficking and uptake function. A possible role for NSF in the pathophysiology of autism through modulation of SERT trafficking, is suggested.
    Molecular Autism 05/2014; 5(1):33. DOI:10.1186/2040-2392-5-33 · 5.41 Impact Factor
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