☆ 4.2 Article

TPH2 5'- and 3'-regulatory polymorphisms are differentially associated with HPA axis function and self-injurious behavior in rhesus monkeys

GENES BRAIN AND BEHAVIOR (2010)

期刊

GENES BRAIN AND BEHAVIOR

卷 9, 期 3, 页码 335-347

出版社

WILEY

DOI: 10.1111/j.1601-183X.2010.00564.x

关键词

Gene expression; HPA axis; regulatory polymorphism; rhesus monkey; self-injurious behavior; self-wounding; self-biting; serotonin; tryptophan hydroxylase-2

类别

Behavioral Sciences Neurosciences

资金

[MH077995]
[MH082507]
[AA016194]
[DA025697]
[RR11122]
[RR00168]

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摘要

Tryptophan hydroxylase-2 (TPH2) synthesizes neuronal serotonin and is linked to numerous behavioral traits. We have previously characterized the functionality of polymorphisms (especially 2051A > C) in 3'-untranslated region (3'-UTR) of rhesus monkey TPH2 (rhTPH2). This study further assessed the functionality of additional polymorphisms (-1605T > C, -1491Tn, -1485(AT)n, -1454A > G, -1325In > Del and -363T > G) in rhTPH2 5'-flanking region (5'-FR), and evaluated the effects of rhTPH2 5' and 3' genotypes on central serotonin turnover, hypothalamic-pituitary-adrenal (HPA) axis function and self-injurious behavior (SIB) in 32 unrelated adult male monkeys of Indian origin. Haplotypes of the rhTPH2 5'-FR polymorphisms exert a significant, cell-dependent effect on reporter gene expression, primarily conferred by -1485(AT)n. The -1485(AT)n and 2051A > C polymorphisms interact to influence cerebrospinal fluid (CSF) 5-HIAA and plasma adrenocorticotropic hormone (ACTH) in the afternoon. While -1485(AT)n exerts significant main effects on the afternoon cortisol level and nocturnal HPA negative feedback, 2051A > C has significant main effects on the morning cortisol level and cortisol response to ACTH challenge, as well as marginally significant main effects on the daytime HPA negative feedback and self-biting rate. In addition, the genotype/allele frequency of the 5'-FR -1325Ins > Del differed significantly between the self-wounders and non-wounders, whereas 3'-UTR 2128S > L polymorphism differed significantly in genotype/allele frequency between the high- and low-frequency biters. This study shows the functionality of rhTPH2 5'-FR polymorphisms, and provides evidence for the differential association of rhTPH2 5'-FR and 3'-UTR polymorphisms with HPA axis function and SIB. Our findings shed light on the role of TPH2 gene variance in physiology and behavioral traits, and also contribute to the understanding of the pathophysiology and genetics of SIB.

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Phenylalanine hydroxylase contributes to serotonin synthesis in mice

Alexander Mordhorst, Priyavathi Dhandapani, Susann Matthes, Valentina Mosienko, Michael Rothe, Mihail Todiras, Julie Self, Wolf-Hagen Schunck, Anja Schutz, Michael Bader, Natalia Alenina

Summary: Serotonin synthesis involves the hydroxylation of tryptophan, with most vertebrates having two known enzymes for this step. However, even in animals lacking these two enzymes, there is still some serotonin production, suggesting the presence of a third enzyme. The study found evidence that phenylalanine hydroxylase (PAH) may act as a third tryptophan hydroxylase in mammals, contributing to serotonin levels in the blood and potentially serving as a local source of serotonin in organs where other TPHs are not expressed.

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