Nakamura Kazuhiro, Sugawara Yuko, Sawabe Keiko, Ohashi Akiko, Tsurui Hiromichi, Xiu Yan, Ohtsuji Mareki, Lin Qing Shun, Nishimura Hiroyuki, Hasegawa Hiroyuki, Hirose Sachiko
Department of Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
J Neurosci. 2006 Jan 11;26(2):530-4. doi: 10.1523/JNEUROSCI.1835-05.2006.
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.
血清素[5-羟色胺（5-HT）]是精神疾病的主要治疗靶点。色氨酸羟化酶（TPH）催化5-HT生物合成中的限速反应。已鉴定出具有色氨酸羟化活性的两种同工型（TPH1和TPH2）。关联研究表明TPH1可能与精神疾病和行为特征有关。然而，据报道TPH1 mRNA主要在松果体和外周表达，在脑中几乎检测不到。因此，TPH1对脑5-HT水平的贡献尚不清楚，其可能导致精神疾病发病机制的方式也未明。在此，我们展示了TPH1在发育中的大脑中的一个意想不到的作用。我们发现TPH1在小鼠大脑发育后期优先表达。在反映发育中脑干情况的条件下，TPH1比TPH2对色氨酸具有更高的亲和力和更强的酶活性。在TPH1基因具有常见功能多态性的新西兰白兔（NZW）和SWR小鼠发育过程中，中缝核中的5-HT含量较低。然而，这些小鼠成年后5-HT含量并未降低。在成年NZW和SWR小鼠中，观察到了与抑郁相关的行为。考虑到发育性脑功能障碍与精神疾病有关，TPH1可能特异性作用于5-HT能神经元的发育，从而影响后期生活中的行为。
