研究会のご案内
リエゾンラボ研究会
発表内容

Title:
MODULATION OF TRYPTOPHAN METABOLISM, PROMOTION OF NEUROGENESISAND ALTERATION OF ANXIETY-RELATED BEHAVIOR IN TRYPTOPHAN 2,3-DIOXYGENASE-DEFICIENT MICE

Hiroshi Funakoshi, M.D., Ph.D.
Dept. Biochemistry & Molecular Biology, and Dept. Microbiology & Immunology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

Abstract:
Tryptophan (Trp) is an essential amino acid that is used for the biosynthesis of proteins and as a precursor for important biological compounds such as serotonin (5-HT), kynurenines, and NAD. Only a small proportion of dietary Trp is used in protein synthesis. The majority of Trp is metabolized along the kynurenine (Kyn) pathway in the liver under normal physiological conditions. The initial and rate-limiting enzyme in the pathway that converts Trp to N-formylkynurenine was initially isolated from rabbit liver and termed tryptophan pyrrolase (Kotake and Masayama, 1936). It was subsequently renamed tryptophan 2,3-dioxygenase (TDO) due to its ability to incorporate atmospheric molecular oxygen into N-formylkynurenine (Hayaishi et al , 1957). TDO was molecularly cloned from a rat liver cDNA library as an open reading frame of 1218 bp (Maezono et al , 1990). In addition to TDO, indoleamine 2,3-dioxygenase (IDO) from rabbit small intestine was found to convert Trp to N-formylkynurenine (Higuchi and Hayaishi, 1967). IDO is thought to function locally outside the liver in sensitive responses to immune signals under highly specific conditions, including pregnancy and autoimmune diseases (Hayaishi, 1993; Mellor and Munn, 2004), while TDO is thought to be an enzyme that functions predominantly in the liver in the physiological regulation of systemic Trp. To elucidate the differential biological role of TDO and IDO, we generated mice deficient for tdo ( Tdo -/- ). Compared with wild-type littermates, Tdo -/- mice showed increased plasma levels of Trp and its metabolites 5-hydroxyindoleacetic acid (5-HIAA) and Kyn as well as increased levels of Trp, 5-HT and 5-HIAA in the hippocampus and midbrain. These mice also showed anxiolytic modulation in the elevated plus maze and open field tests, and increased adult neurogenesis, as evidenced by double staining of BrdU and neural progenitor/neuronal markers. These findings demonstrate that TDO plays an essential role in the homeostasis of systemic and brain Trp metabolism, including the dominant regulation of serotonergic pathway, under the physiological conditions. TDO also play a role in the maintenance of brain morphology via regulating adult neurogenesis in the hippocampus and subventricular zone. Furthermore, TDO modulates anxiety-related behavior, indicating a role of TDO in higher brain functions. We will also briefly present our recent findings in the identification of a homozygous loss-of-function type TDO mutation in a psychiatric disorder in human. Collectively, our findings indicate a direct molecular link between tryptophan metabolism and mental status. Tdo -/- mice will likely prove useful in clarifying the physiological role of Trp metabolism, in normal brain function and psychiatric disorders and in development of new approaches for therapeutic interventions of mental disorders.