Modulation of Tryptophan Metabolism, Pomotion of Neurogenesis and Alteration of Anxiety-Related Behavior in Tryptophan 2,3-Dioxygenase-Deficient Mice

Although tryptophan (Trp) and its metabolites, such as serotonin (5-HT) and kynurenines (KYNs), are strong modulators of emotional behavior, the metabolic pathway(s) responsible for this physiological modulation is not fully understood. Two of the initial rate-limiting enzymes of the kynurenine pathway for Trp metabolism are known: tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Based on our comparison of tdo-deficient (Tdo(−/−)) mice with their wild-type littermates, we report that TDO is the physiological modulator of systemic Trp, brain Trp and serotonin (5-HT), and, therefore, anxiety-related behavior. Tdo(−/−) mice showed increased plasma concentrations of Trp (about 10-fold) and its metabolites 5-hydroxyindoleacetic acid (5-HIAA) and kynurenine, as well as increased levels of Trp (about 20-fold), 5-HT and 5-HIAA in the hippocampus and midbrain. The Tdo(−/−) mice also showed anxiolytic modulation in the elevated plus maze and open field tests, and increased neurogenesis during adulthood, as evidenced by double staining with 5-bromo-2′-deoxyuridine (BrdU) and neural progenitor/neuronal markers. TDO also plays a role in the maintenance of brain morphology in adult animals by regulating neurogenesis in the hippocampus and subventricular zone. Collectively, our results in Tdo(−/−) mice indicate a direct molecular link between Trp metabolism and mental status in mice. Tdo(−/−) mice will likely prove useful both in identifying the physiological role of Trp metabolism in normal brain function and in psychiatric disorders and in developing new therapeutic interventions for mental disorders. In addition, the potential role(s) and molecular mechanisms of TDO in metabolic mental disease(s) and in emotional behavior are discussed.