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

Cross, Sarah J.; Kim, Soo Jeong; Weiss, Lauren A.; Delahanty, Ryan; Sutcliffe, James S.; Leventhal, Bennett L.; Cook, Edwin H.; Veenstra‐VanderWeele, Jeremy

doi:10.1038/sj.npp.1301406

Cited by 59 publications

(44 citation statements)

References 48 publications

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“…In the blood, 5-HT is contained almost exclusively in platelets, which acquire 5-HT through the SERT as they pass through the gut circulation. Not surprisingly, whole-blood 5-HT levels are correlated with SERT-mediated 5-HT uptake (Cook et al, 1993;Cross et al, 2008). Additional abnormalities have been found in the platelet in ASD, including decreased radioligand binding to the 5-HT 2A receptor (Cook et al, 1993;McBride et al, 1989).…”

Section: Biomarkers In Asdmentioning

confidence: 90%

Networking in Autism: Leveraging Genetic, Biomarker and Model System Findings in the Search for New Treatments

Veenstra‐VanderWeele

Blakely

2011

Neuropsychopharmacol

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111

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Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder affecting approximately 1% of children. ASD is defined by core symptoms in two domains: negative symptoms of impairment in social and communication function, and positive symptoms of restricted and repetitive behaviors. Available treatments are inadequate for treating both core symptoms and associated conditions. Twin studies indicate that ASD susceptibility has a large heritable component. Genetic studies have identified promising leads, with converging insights emerging from single-gene disorders that bear ASD features, with particular interest in mammalian target of rapamycin (mTOR)-linked synaptic plasticity mechanisms. Mouse models of these disorders are revealing not only opportunities to model behavioral perturbations across species, but also evidence of postnatal rescue of brain and behavioral phenotypes. An intense search for ASD biomarkers has consistently pointed to elevated platelet serotonin (5-HT) levels and a surge in brain growth in the first 2 years of life. Following a review of the diversity of ASD phenotypes and its genetic origins and biomarkers, we discuss opportunities for translation of these findings into novel ASD treatments, focusing on mTor-and 5-HT-signaling pathways, and their possible intersection. Paralleling the progress made in understanding the root causes of rare genetic syndromes that affect cognitive development, we anticipate progress in models systems using bona fide ASD-associated molecular changes that have the potential to accelerate the development of ASD diagnostics and therapeutics.

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Section: Biomarkers In Asdmentioning

confidence: 90%

Networking in Autism: Leveraging Genetic, Biomarker and Model System Findings in the Search for New Treatments

Veenstra‐VanderWeele

Blakely

2011

Neuropsychopharmacol

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111

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“…Rather, platelets express SERT proteins (the same gene produces SERT proteins in platelets and brain (Lesch et al 1993)), to acquire 5-HT released into the circulation by enterochromaffin cells of the gut. Importantly, just as autism risk, blood 5-HT levels are heritable (Cross et al 2008), suggesting that shared alleles at the SLC6A4 locus and other 5-HT determining genes may explain components of both traits in some autism subjects.…”

Section: Introductionmentioning

confidence: 99%

Enhanced activity of human serotonin transporter variants associated with autism

Prasad

Steiner

Sutcliffe

et al. 2008

Phil. Trans. R. Soc. B

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119

111

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Rare, functional, non-synonymous variants in the human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT) gene (SLC6A4) have been identified in both autism and obsessive-compulsive disorder (OCD). Within autism, rare hSERT coding variants associate with rigid-compulsive traits, suggesting both phenotypic overlap with OCD and a shared relationship with disrupted 5-HT signalling. Here, we document functional perturbations of three of these variants: Ile425Leu; Phe465Leu; and Leu550Val. In transiently transfected HeLa cells, the three variants confer a gain of 5-HT transport phenotype. Specifically, enhanced SERT activity was also observed in lymphoblastoid lines derived from mutation carriers. In contrast to previously characterized Gly56Ala, where increased transport activity derives from catalytic activation, the three novel variants exhibit elevated surface density as revealed through both surface antagonist-binding and biotinylation studies. Unlike Gly56Ala, mutants Ile425Leu, Phe465Leu and Leu550Val retain a capacity for acute PKG and p38 MAPK regulation. However, both Gly56Ala and Ile425Leu demonstrate markedly reduced sensitivity to PP2A antagonists, suggesting that deficits in trafficking and catalytic modulation may derive from a common basis in perturbed phosphatase regulation. When expressed stably from the same genomic locus in CHO cells, both Gly56Ala and Ile425Leu display catalytic activation, accompanied by a striking loss of SERT protein.

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“…Evidence documenting the association of ITGB3 with whole blood 5-HT levels, replicated by multiple laboratories (Weiss Integrin β3 modulates CNS SERT function in mice M Mazalouskas et al , 2006a, 2006bCoutinho et al, 2007;Cross et al, 2008;Napolioni et al, 2011) led us to examine whether haploinsufficiency in the integrin β3 gene modulates SERT function in the CNS. In contrast to studies in platelets, disruption of a single Itgb3 allele in mice was sufficient to dramatically diminish 5-HT uptake by SERT in raphe synaptosomes, indicating that serotonergic signaling in the CNS is more sensitive to alterations in integrin β3 subunit expression (Carneiro et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…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(Weiss et al, , 2006aCoutinho 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).…”

Section: Introductionmentioning

confidence: 99%

Integrin β3 Haploinsufficiency Modulates Serotonin Transport and Antidepressant-Sensitive Behavior in Mice

Mazalouskas

Jessen

Varney

et al. 2015

Neuropsychopharmacol

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Converging lines of evidence have identified genetic interactions between the serotonin transporter (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-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI) effectiveness in vivo. Biochemical fractionation studies and immunofluorescent staining of murine brain slices reveal that αvβ3 receptors and SERTs 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.

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

Cited by 59 publications

References 48 publications

Networking in Autism: Leveraging Genetic, Biomarker and Model System Findings in the Search for New Treatments

Networking in Autism: Leveraging Genetic, Biomarker and Model System Findings in the Search for New Treatments

Enhanced activity of human serotonin transporter variants associated with autism

Integrin β3 Haploinsufficiency Modulates Serotonin Transport and Antidepressant-Sensitive Behavior in Mice

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