Late developmental stage-specific role of tryptophan hydroxylase 1 in brain serotonin levels.
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.
Nakamura
Kazuhiro
K
Department of Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan. kaz@med.juntendo.ac.jp
Sugawara
Yuko
Y
Sawabe
Keiko
K
Ohashi
Akiko
A
Tsurui
Hiromichi
H
Xiu
Yan
Y
Ohtsuji
Mareki
M
Lin
Qing Shun
QS
Nishimura
Hiroyuki
H
Hasegawa
Hiroyuki
H
Hirose
Sachiko
S
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D001921:Brain / Q000201:enzymology* / Q000254:growth & development; D019556:COS Cells; D002522:Chlorocebus aethiops; D003863:Depression / Q000188:drug therapy / Q000235:genetics / Q000523:psychology; D004790:Enzyme Induction; D046352:Freezing Reaction, Cataleptic; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007099:Imipramine / Q000627:therapeutic use; D051379:Mice; D008815:Mice, Inbred Strains; D017374:Paroxetine / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D011903:Raphe Nuclei / Q000254:growth & development / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012701:Serotonin / Q000096:biosynthesis* / Q000172:deficiency; D014364:Tryptophan / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000032:analysis / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000928:Antidepressive Agents; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D001708:Biopterins; D012701:Serotonin; D017374:Paroxetine; D014364:Tryptophan; C487801:Tph1 protein, mouse; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; C003402:sapropterin; D007099:Imipramine