TY - JOUR
T1 - Deficiency of kynurenine 3-monooxygenase exacerbates impairment of prepulse inhibition induced by phencyclidine
AU - Kubota, Hisayoshi
AU - Kunisawa, Kazuo
AU - Niijima, Moe
AU - Hirakawa, Mami
AU - Mori, Yuko
AU - Hasegawa, Masaya
AU - Fujigaki, Suwako
AU - Fujigaki, Hidetsugu
AU - Yamamoto, Yasuko
AU - Saito, Kuniaki
AU - Nabeshima, Toshitaka
AU - Mouri, Akihiro
N1 - Funding Information:
This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science ( 17H04252 , 20K07931 , and 20K16679 ), the Private University Research Branding Project from the Ministry of Education, Culture, Sports, Science, and Technology of Japan ( MEXT ), and the Japan Science and Technology Agency ( JST ) FOREST Program ( JPMJFR215H ). This work was supported by a grant from the Education and Research Facility of Animal Models for Human Diseases at Fujita Health University , a research grant from the Smoking Research Foundation , and the Takeda Science Foundation . We thank our lab members for their helpful discussions. We would like to thank Editage ( www.editage.com ) for the English language editing.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/11/12
Y1 - 2022/11/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.bbrc.2022.09.003
DO - 10.1016/j.bbrc.2022.09.003
M3 - Article
C2 - 36116377
AN - SCOPUS:85137858952
VL - 629
SP - 142
EP - 151
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
ER -