Research
Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice
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* Corresponding author: Toshikazu Nakamura nakamura@casi.osaka-u.ac.jp
1 Division of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
2 Department of Molecular and Cellular Biology, School of Medicine, Ehime University, Ehime, Japan
3 Department of Vascular Regeneration, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
4 Division of Tumor Dynamics and Regulation, Kanazawa University Cancer Research Institute, Kanazawa, Japan
5 Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Osaka University, Osaka 565-0871, Japan
Molecular Brain 2009, 2:8 doi:10.1186/1756-6606-2-8
Published: 27 March 2009Abstract
Although nutrients, including amino acids and their metabolites such as serotonin (5-HT), are strong modulators of anxiety-related behavior, the metabolic pathway(s) responsible for this physiological modulation is not fully understood. Regarding tryptophan (Trp), the initial rate-limiting enzymes for the kynurenine pathway of tryptophan metabolism are tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Here, 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 kynurenine, 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 a direct molecular link between Trp metabolism and neurogenesis and anxiety-related behavior under physiological conditions.