Late Developmental Stage-specific Role of Tryptophan Hydroxylase 1 in Brain Serotonin Levels

Overview

Journal J Neurosci

Specialty Neurology

Date 2006 Jan 13

PMID 16407550

Citations 43

Authors

Kazuhiro Nakamura

Yuko Sugawara

Keiko Sawabe

Akiko Ohashi

Hiromichi Tsurui

Yan Xiu

Mareki Ohtsuji

Qing Shun Lin

Hiroyuki Nishimura

Hiroyuki Hasegawa

Sachiko Hirose

Affiliations

Soon will be listed here.

Abstract

Serotonin [5-hydroxytryptamine (5-HT)] is a major therapeutic target of psychiatric disorders. Tryptophan hydroxylase (TPH) catalyzes the rate-limiting reaction in the biosynthesis of 5-HT. Two isoforms (TPH1 and TPH2) having tryptophan hydroxylating activity were identified. Association studies have revealed possible TPH1 involvement in psychiatric conditions and behavioral traits. However, TPH1 mRNA was reported to be mainly expressed in the pineal gland and the periphery and to be barely detected in the brain. Therefore, contribution of TPH1 to brain 5-HT levels is not known, and the mechanisms how TPH1 possibly contributes to the pathogenesis of psychiatric disorders are not understood. Here, we show an unexpected role of TPH1 in the developing brain. We found that TPH1 is expressed preferentially during the late developmental stage in the mouse brain. TPH1 showed higher affinity to tryptophan and stronger enzyme activity than TPH2 in a condition reflecting that of the developing brainstem. Low 5-HT contents in the raphe nucleus were seen during development in New Zealand white (NZW) and SWR mice having common functional polymorphisms in the TPH1 gene. However, the 5-HT contents in these mice were not reduced in adulthood. In adult NZW and SWR mice, depression-related behavior was observed. Considering an involvement of developmental brain disturbance in psychiatric disorders, TPH1 may act specifically on development of 5-HT neurons, and thereby influence behavior later in life.

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References

Shih J, Chen K, Ridd M . Monoamine oxidase: from genes to behavior. Annu Rev Neurosci. 1999; 22:197-217. PMC: 2844879. DOI: 10.1146/annurev.neuro.22.1.197. View

Dulawa S, Gross C, Stark K, Hen R, Geyer M . Knockout mice reveal opposite roles for serotonin 1A and 1B receptors in prepulse inhibition. Neuropsychopharmacology. 2000; 22(6):650-9. DOI: 10.1016/S0893-133X(99)00164-5. View

Rind H, Russo A, Whittemore S . Developmental regulation of tryptophan hydroxylase messenger RNA expression and enzyme activity in the raphe and its target fields. Neuroscience. 2000; 101(3):665-77. DOI: 10.1016/s0306-4522(00)00402-4. View

Luna B, Sweeney J . Studies of brain and cognitive maturation through childhood and adolescence: a strategy for testing neurodevelopmental hypotheses. Schizophr Bull. 2001; 27(3):443-55. DOI: 10.1093/oxfordjournals.schbul.a006886. View

Iida Y, Sawabe K, Kojima M, Oguro K, Nakanishi N, Hasegawa H . Proteasome-driven turnover of tryptophan hydroxylase is triggered by phosphorylation in RBL2H3 cells, a serotonin producing mast cell line. Eur J Biochem. 2002; 269(19):4780-8. DOI: 10.1046/j.1432-1033.2002.03188.x. View

Gainetdinov R, Caron M . Monoamine transporters: from genes to behavior. Annu Rev Pharmacol Toxicol. 2002; 43:261-84. DOI: 10.1146/annurev.pharmtox.43.050802.112309. View

Walther D, Peter J, Bashammakh S, Hortnagl H, Voits M, Fink H . Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science. 2003; 299(5603):76. DOI: 10.1126/science.1078197. View

Rujescu D, Giegling I, Sato T, Hartmann A, Moller H . Genetic variations in tryptophan hydroxylase in suicidal behavior: analysis and meta-analysis. Biol Psychiatry. 2003; 54(4):465-73. DOI: 10.1016/s0006-3223(02)01748-1. View

Cote F, Thevenot E, Fligny C, Fromes Y, Darmon M, Ripoche M . Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc Natl Acad Sci U S A. 2003; 100(23):13525-30. PMC: 263847. DOI: 10.1073/pnas.2233056100. View

10.

Gaspar P, Cases O, Maroteaux L . The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci. 2003; 4(12):1002-12. DOI: 10.1038/nrn1256. View

11.

Bellivier F, Chaste P, Malafosse A . Association between the TPH gene A218C polymorphism and suicidal behavior: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2003; 124B(1):87-91. DOI: 10.1002/ajmg.b.20015. View

12.

Peters E, Slager S, McGrath P, Knowles J, Hamilton S . Investigation of serotonin-related genes in antidepressant response. Mol Psychiatry. 2004; 9(9):879-89. DOI: 10.1038/sj.mp.4001502. View

13.

Lesch K . Gene-environment interaction and the genetics of depression. J Psychiatry Neurosci. 2004; 29(3):174-84. PMC: 400687. View

14.

Zhang X, Beaulieu J, Sotnikova T, Gainetdinov R, Caron M . Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science. 2004; 305(5681):217. DOI: 10.1126/science.1097540. View

15.

Sawabe K, Wakasugi K, Hasegawa H . Tetrahydrobiopterin uptake in supplemental administration: elevation of tissue tetrahydrobiopterin in mice following uptake of the exogenously oxidized product 7,8-dihydrobiopterin and subsequent reduction by an anti-folate-sensitive process. J Pharmacol Sci. 2004; 96(2):124-33. DOI: 10.1254/jphs.fp0040280. View

16.

McKinney J, Knappskog P, Haavik J . Different properties of the central and peripheral forms of human tryptophan hydroxylase. J Neurochem. 2005; 92(2):311-20. DOI: 10.1111/j.1471-4159.2004.02850.x. View

17.

Niwa H, Yamamura K, Miyazaki J . Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene. 1991; 108(2):193-9. DOI: 10.1016/0378-1119(91)90434-d. View

18.

Stoll J, Goldman D . Isolation and structural characterization of the murine tryptophan hydroxylase gene. J Neurosci Res. 1991; 28(4):457-65. DOI: 10.1002/jnr.490280402. View

19.

Hasegawa H, ICHIYAMA A . Tryptophan 5-monooxygenase from mouse mastocytoma: high-performance liquid chromatography assay. Methods Enzymol. 1987; 142:88-92. DOI: 10.1016/s0076-6879(87)42013-2. View

20.

Steru L, Chermat R, Thierry B, Simon P . The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl). 1985; 85(3):367-70. DOI: 10.1007/BF00428203. View