RT Journal Article
SR Electronic
T1 Late Developmental Stage-Specific Role of Tryptophan Hydroxylase 1 in Brain Serotonin Levels
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 530
OP 534
DO 10.1523/JNEUROSCI.1835-05.2006
VO 26
IS 2
A1 Nakamura, Kazuhiro
A1 Sugawara, Yuko
A1 Sawabe, Keiko
A1 Ohashi, Akiko
A1 Tsurui, Hiromichi
A1 Xiu, Yan
A1 Ohtsuji, Mareki
A1 Lin, Qing Shun
A1 Nishimura, Hiroyuki
A1 Hasegawa, Hiroyuki
A1 Hirose, Sachiko
YR 2006
UL http://www.jneurosci.org/content/26/2/530.abstract
AB 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.