Deficiency of kynurenine 3-monooxygenase exacerbates impairment of prepulse inhibition induced by phencyclidine
Deficiency of kynurenine 3-monooxygenase exacerbates impairment of prepulse inhibition induced by phencyclidine
复制标题
犬尿氨酸 3-单加氧酶的缺乏加剧了苯环己哌啶诱导的前脉冲抑制的损害
DOI：
10.1016/j.bbrc.2022.09.003
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发表时间：
2022
影响因子：
3.1
通讯作者：
Mouri Akihiro
中科院分区：
文献类型：
--
作者：
Kubota Hisayoshi;Kunisawa Kazuo;Niijima Moe;Hirakawa Mami;Mori Yuko;Hasegawa Masaya;Fujigaki Suwako;Fujigaki Hidetsugu;Yamamoto Yasuko;Saito Kuniaki;Nabeshima Toshitaka;Mouri Akihiro
Phencyclidine (PCP) causes mental symptoms that closely resemble schizophrenia through the inhibition of the glutamatergic system. The kynurenine (KYN) pathway (KP) generates metabolites that modulate glutamatergic systems such as kynurenic acid (KA), quinolinic acid (QA), and xanthurenic acid (XA). Kynurenine 3-monooxygenase (KMO) metabolizes KYN to 3-hydroxykynurenine (3-HK), an upstream metabolite of QA and XA. Clinical studies have reported lower KMO mRNA and higher KA levels in the postmortem brains of patients with schizophrenia and exacerbation of symptoms in schizophrenia by PCP. However, the association between KMO deficiency and PCP remains elusive. Here, we demonstrated that a non-effective dose of PCP induced impairment of prepulse inhibition (PPI) in KMO KO mice. KA levels were increased in the prefrontal cortex (PFC) and hippocampus (HIP) of KMO KO mice, but 3-HK levels were decreased. In wild-type C57BL/6 N mice, the PPI impairment induced by PCP is exacerbated by KA, while attenuated by 3-HK, QA and XA. Taken together, KMO KO mice were vulnerable to the PPI impairment induced by PCP through an increase in KA and a decrease in 3-HK, suggesting that an increase in the ratio of KA to 3-HK (QA and XA) may play an important role in the pathophysiology of schizophrenia.
