Modulation of Tryptophan Metabolism, Pomotion of Neurogenesis and Alteration of Anxiety-Related Behavior in Tryptophan 2,3-Dioxygenase-Deficient Mice
Modulation of Tryptophan Metabolism, Pomotion of Neurogenesis and Alteration of Anxiety-Related Behavior in Tryptophan 2,3-Dioxygenase-Deficient Mice
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色氨酸代谢的调节，神经发生的促进和色氨酸2,3-二氧酶缺陷型小鼠的焦虑相关行为的改变
DOI：
10.4137/ijtr.s5783
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发表时间：
2011-04-11
期刊：
影响因子：
--
通讯作者：
Nakamura T
中科院分区：
文献类型：
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作者：
Funakoshi H;Kanai M;Nakamura T
尽管色氨酸(Trp)及其代谢产物5-羟色胺(5-HT)和犬尿氨酸(KYN)是情绪行为的强大调节器，但负责这种生理调节的代谢途径(S)尚不完全清楚。目前已知犬尿氨酸代谢途径中的两种限速酶：色氨酸2，3-双加氧酶(TDO)和吲哚胺2，3-双加氧酶(IDO)。基于我们对Tdo缺陷(Tdo-−/−)小鼠和它们的野生型小鼠的比较，我们报告了Tdo是全身色氨酸、脑色氨酸和5-羟色胺(5-HT)的生理调节器，因此，焦虑相关行为。Tdo−/−小鼠的血浆色氨酸及其代谢产物5-羟吲哚乙酸(5-HIAA)和犬尿氨酸的浓度增加了约10倍，海马区和中脑的色氨酸、5-羟色胺和5-HIAA的浓度也增加了约20倍。通过5-溴-2‘-脱氧尿嘧啶核苷(BrdU)和神经前体/神经元标记物的双重染色，Tdo−/−小鼠在高架+迷宫和旷场测试中也表现出抗焦虑的调节作用，并在成年后增加了神经发生。TDO还通过调节海马区和脑室下区的神经发生，在维持成年动物的大脑形态方面发挥作用。总而言之，我们在Tdo−/−小鼠身上的结果表明，色氨酸代谢与小鼠的精神状态之间存在直接的分子联系。Tdo−/−小鼠可能会被证明在确定色氨酸代谢在正常大脑功能和精神疾病中的生理作用以及开发新的精神障碍治疗干预措施方面都是有用的。此外，还讨论了TDO在代谢性精神疾病(S)和情绪行为中的潜在作用(S)和分子机制。
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.