Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders.
Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders.
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DOI：
10.1016/j.biopsych.2016.12.011
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发表时间：
2017-11-15
影响因子：
10.6
通讯作者：
Schwarcz R
中科院分区：
文献类型：
--
作者：
Erhardt S;Pocivavsek A;Repici M;Liu XC;Imbeault S;Maddison DC;Thomas MAR;Smalley JL;Larsson MK;Muchowski PJ;Giorgini F;Schwarcz R
犬尿氨酸3-单加氧酶（KMO）将犬尿氨酸转化为3-羟基犬尿氨酸，它的抑制使犬尿氨酸通路（与各种精神疾病有关的功能障碍）转向增强犬尿氨酸（KYNA）的合成，KYNA是α7烟碱乙酰胆碱和NMDA受体的拮抗剂。可能是KMO活性降低的结果，在包括精神分裂症（SZ）在内的精神病患者中发现了中枢神经系统KYNA水平升高。在本研究中，我们研究了靶向缺失Kmo （Kmo - / -）小鼠的适应性和可能的调节性变化，并使用与SZ研究相关的六种行为测定来表征Kmo缺陷小鼠。在这些小鼠的大脑皮层和小脑中进行的全基因组差异基因表达分析发现了SZ和精神病相关基因网络，在小脑组织中有更明显的改变。Kmo - / -小鼠这些脑区的KYNA水平也增加，小脑的水平明显高于大脑。与对照组相比，Kmo - / -小鼠在社交互动范式中与不熟悉的小鼠互动的时间更少，并且在情境记忆方面表现出损伤。突变动物在高加迷宫和明暗盒子中表现出更多的焦虑样行为。在d -安非他明刺激（5mg /kg, i.p.）后，Kmo - / -小鼠在开阔场范式中表现出增强的水平活性。综上所述，这些结果表明，小鼠中Kmo的消除与多种基因和功能改变有关，这些改变似乎重复了几种神经精神疾病的精神病理方面。
Kynurenine 3-monooxygenase (KMO) converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway - which is implicated as dysfunctional in various psychiatric disorders - towards enhanced synthesis of kynurenic acid (KYNA), an antagonist of both α7 nicotinic acetylcholine and NMDA receptors. Possibly as a result of reduced KMO activity, elevated central nervous system levels of KYNA have been found in patients with psychotic disorders, including schizophrenia (SZ). In the present study, we investigated adaptive – and possibly regulatory – changes in mice with a targeted deletion of Kmo (Kmo−/−) and characterized the KMO-deficient mice using six behavioral assays relevant for the study of SZ. Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of SZ- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. KYNA levels were also increased in these brain regions in Kmo−/− mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo−/− mice exhibited impairments in contextual memory and spent less time than controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light-dark box. After a D-amphetamine challenge (5 mg/kg, i.p.), Kmo−/− mice showed potentiated horizontal activity in the open field paradigm. Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders.
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影响因子：
10.6
作者：
Erhardt, S;Schwieler, L;Geyer, M
通讯作者：
Geyer, M
影响因子：
2.5
作者：
Erhardt, S;Blennow, K;Engberg, G
通讯作者：
Engberg, G
影响因子：
3.3
作者：
CARPENEDO, R;CHIARUGI, A;MATTOLI, L
通讯作者：
MATTOLI, L
影响因子：
11.3
作者：
Hasenkamp, Wendy;Kelley, Mary;Egan, Glenn;Green, Amanda;Wilcox, Lisette;Boshoven, William;Lewison, Barbara;Duncan, Erica
通讯作者：
Duncan, Erica
影响因子：
2.5
作者：
Aoyama, N.;Takahashi, N.;Ozaki, N.
通讯作者：
Ozaki, N.