Neurochemical, behavioral, and genetic evidence implicate serotonergic dysfunction in autism, andspecifically in restricted and repetitive behaviors (RRBs). Discovery of elevated platelet serotonin (5HT) in~25-30% of individuals with autism is one of the seminal findings in neuropsychiatric research. Autism is themost heritable complex neuropsychiatric disorder, and platelet 5HT levels are also extremely heritable.Further, elevated platelet 5HT is associated with recurrence risk, both in autism and in obsessive compulsivedisorder (OCD). The relationship between autism and OCD is underscored by correlations between RRBs inprobands with autism and parental OC symptoms. Recently described mutations in the serotonin transporter(SERT) gene (SLC6A4) result in a common pattern of elevated 5HT transporter activity and a phenotype ofautism with RRBs or OCD. Many studies have sought to test for genetic effects at SLC6A4, but the field hasbeen limited by the lack of robust measures of RRBs in autism and key platelet markers of serotonergicfunction. Indices of Insistence on Sameness (IS) now allow RRB symptoms to be included in geneticanalysis. Deciphering the relationships between autism and 5HT requires critical neurochemical phenotypesfor elucidation of the underlying mechanisms. For example, our studies of platelet 5HT levels in inbred andoutbred populations point to the integrin (53 gene (ITGB3) as a quantitative trait locus for platelet 5HT.Follow-up studies demonstrate association between ITGB3 and autism directly. Preliminary data furthershow that SERT and ITGB3 physically interact in platelets, and that absence of ItgbS in mouse brainsignificantly diminishes SERT activity. Other studies find that decreased platelet 5HT2A correlates betweenboys with autism and their fathers and parallels decreased binding in recent brain studies. We proposefurther study of SLC6A4, ITGBS and HTR2A to evaluate common and rare variation contributing to adysregulated 5HT system, IS, and autism. Given strong evidence supporting 5HT involvement generally andthese three components specifically, we hypothesize that other variation within 5HT-related genes is verylikely to contribute to autism risk as well. We propose to systematically assess the role of 5HT-related genesin autism by using the critical neurochemical and behavioral measures to provide the phenotype data mostlikely to index genetic liability related to this system
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