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The Journal of Neuroscience, January 11, 2006, 26(2):530-534; doi:10.1523/JNEUROSCI.1835-05.2006

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

Kazuhiro Nakamura,¹ Yuko Sugawara,² Keiko Sawabe,² Akiko Ohashi,² Hiromichi Tsurui,¹ Yan Xiu,¹ Mareki Ohtsuji,¹ Qing Shun Lin,¹ Hiroyuki Nishimura,³ Hiroyuki Hasegawa,² and Sachiko Hirose¹

¹Department of Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan, ²Department of Bioscience, Teikyo University of Science and Technology, Uenohara, Yamanashi 409-0193, Japan, and ³Department of Biomedical Engineering, Toin Human Science and Technology Center, Toin University of Yokohama, Yokohama 225-8502, Japan

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.

Key words: behavior; depression; RAPHE; serotonin; tryptophan hydroxylase; development

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Received May 7, 2005; revised August 16, 2005; accepted November 21, 2005.

This article has been cited by other articles:

				J. E. Tanis, J. J. Moresco, R. A. Lindquist, and M. R. Koelle Regulation of Serotonin Biosynthesis by the G Proteins G{alpha}o and G{alpha}q Controls Serotonin Signaling in Caenorhabditis elegans Genetics, January 1, 2008; 178(1): 157 - 169. [Abstract] [Full Text] [PDF]

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