Perturbation of monoamine metabolism and enhanced fear responses in mice defective in the regeneration of tetrahydrobiopterin
Perturbation of monoamine metabolism and enhanced fear responses in mice defective in the regeneration of tetrahydrobiopterin
复制标题
DOI：
10.1111/jnc.15600
复制
发表时间：
2022-03
影响因子：
4.7
通讯作者：
Katsuya Miyajima;Y. Sudo;Sho Sanechika;Y. Hara;Mieko Horiguchi;F. Xu;Minori Suzuki;Satoshi Hara;Koichi Tanda;Ken-ichi Inoue;M. Takada;Nozomu Yoshioka;H. Takebayashi;Masayo Mori-Kojima;M. Sugimoto;C. Sumi-Ichinose;Kazunao Kondo;K. Takao;T. Miyakawa;H. Ichinose
中科院分区：
文献类型：
--
作者：
Katsuya Miyajima;Y. Sudo;Sho Sanechika;Y. Hara;Mieko Horiguchi;F. Xu;Minori Suzuki;Satoshi Hara;Koichi Tanda;Ken-ichi Inoue;M. Takada;Nozomu Yoshioka;H. Takebayashi;Masayo Mori-Kojima;M. Sugimoto;C. Sumi-Ichinose;Kazunao Kondo;K. Takao;T. Miyakawa;H. Ichinose
越来越多的证据表明，外周氨基酸代谢参与了神经精神障碍的病理生理学，但其分子机制在很大程度上尚不清楚。四氢生物蝶呤(BH4)是催化苯丙氨酸代谢、单胺合成、一氧化氮产生和脂质代谢的酶的辅因子。BH4是以鸟苷三磷酸为原料合成的，在喹酮类二氢蝶啶还原酶(QDPR)的作用下再生，该酶催化喹酮类二氢生物蝶呤的还原。我们对Qdpr−/−小鼠进行了分析，以阐明BH4再生的生理意义。我们发现Qdpr−/−小鼠表现出轻微的高苯丙氨酸血症和大脑中单胺缺乏，尽管肝脏和大脑中存在大量的BH4。外源性给予BH4可改善高苯丙氨酸血症，饮食苯丙氨酸限制可有效恢复Qdpr−/−小鼠脑内单胺含量的下降，提示高苯丙氨酸血症的继发作用是导致单胺缺乏症的原因。免疫组织化学分析表明，QDPR主要分布在少突胶质细胞中，而在脑内单胺能神经元中几乎检测不到。最后，我们使用测试电池进行了行为评估。Qdpr−/−小鼠在脚部电击后表现出增强的恐惧反应。综上所述，我们的数据表明，BH4代谢的扰动应该通过改变外周氨基酸代谢来影响大脑单胺水平，并可能有助于与焦虑相关的精神障碍的发展。
Increasing evidence suggests the involvement of peripheral amino acid metabolism in the pathophysiology of neuropsychiatric disorders, whereas the molecular mechanisms are largely unknown. Tetrahydrobiopterin (BH4) is a cofactor for enzymes that catalyze phenylalanine metabolism, monoamine synthesis, nitric oxide production, and lipid metabolism. BH4 is synthesized from guanosine triphosphate and regenerated by quinonoid dihydropteridine reductase (QDPR), which catalyzes the reduction of quinonoid dihydrobiopterin. We analyzed Qdpr−/− mice to elucidate the physiological significance of the regeneration of BH4. We found that the Qdpr−/− mice exhibited mild hyperphenylalaninemia and monoamine deficiency in the brain, despite the presence of substantial amounts of BH4 in the liver and brain. Hyperphenylalaninemia was ameliorated by exogenously administered BH4, and dietary phenylalanine restriction was effective for restoring the decreased monoamine contents in the brain of the Qdpr−/− mice, suggesting that monoamine deficiency was caused by the secondary effect of hyperphenylalaninemia. Immunohistochemical analysis showed that QDPR was primarily distributed in oligodendrocytes but hardly detectable in monoaminergic neurons in the brain. Finally, we performed a behavioral assessment using a test battery. The Qdpr−/− mice exhibited enhanced fear responses after electrical foot shock. Taken together, our data suggest that the perturbation of BH4 metabolism should affect brain monoamine levels through alterations in peripheral amino acid metabolism, and might contribute to the development of anxiety‐related psychiatric disorders.