Article

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

ABSTRACT

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.
    No preview · Article · Feb 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
    • "Accumulating evidences suggest that SLC6A4 variants possibly regulate behavioral phenotype by maintaining the 5-HT level in the CNS. While four studies indicated lack of correlation of 5-HTTLPR with platelet 5-HT content (Anderson et al., 2002; Betancur et al., 2002; Cross et al., 2008; Napolioni et al., 2011), two reports suggested association of 5-HTTLPR and STin2 with increased risk of platelet hyperserotonemia in autism (Coutinho et al., 2004, 2007). However, such studies are lacking in the Indian population. "
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    ABSTRACT: Presence of platelet hyperserotonemia and effective amelioration of behavioral dysfunctions by selective serotonin reuptake inhibitors (SSRI) in autism spectrum disorders (ASD) indicate that irregularities in serotonin (5-HT) reuptake and its homeostasis could be the basis of behavioral impairments in ASD patients. SLC6A4, the gene encoding serotonin transporter (SERT) is considered as a potential susceptibility gene for ASD, since it is a quantitative trait locus for blood 5-HT levels. Three functional polymorphisms, 5-HTTLPR, STin2 and 3'UTR-SNP of SLC6A4 are extensively studied for possible association with the disorder, with inconclusive outcome. In the present study, we investigated association of these polymorphisms with platelet 5-HT content and symptoms severity as revealed by childhood autism rating scale in ASD children from an Indian population. Higher 5-HT level observed in ASD was highly significant in children with heterozygous and homozygous genotypes comprising of minor alleles of the markers. Quantitative transmission disequilibrium test demonstrated significant genetic effect of STin2 allele as well as STin2/3'UTR-SNP and 5-HTTLPR/3'UTR-SNP haplotypes on 5-HT levels, but no direct association with overall CARS score and ASD phenotype. Significant genetic effect of the markers on specific behavioral phenotypes was observed for various sub-phenotypes of CARS in quantitative trait analysis. Even though the 5-HT level was not associated with severity of behavioral CARS score, a significant negative relationship was observed for 5-HT levels and level and consistency of intellectual response and general impression in ASD children. Population-based study revealed higher distribution of the haplotype 10/G of STin2/3'-UTR in male controls, suggesting protective effect of this haplotype in male cases. Overall results of the study suggest that SLC6A4 markers have specific genetic effect on individual ASD behavioral attributes, might be through the modulation of 5-HT content.
    No preview · Article · Sep 2014 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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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.
    Full-text · Article · Aug 2014 · Frontiers in Cellular Neuroscience
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