Xu Haiyun, Yang Hong-Ju, Zhang Yanbo, Clough Richard, Browning Ronald, Li Xin-Min
School of Medicine, Southern Illinois University Carbondale, Carbondale, IL 62901, USA.
Behav Neurosci. 2009 Apr;123(2):418-29. doi: 10.1037/a0014477.
C57BL/6 mice were given 0.2% cuprizone (CPZ) for 2 to 6 weeks while controls ate the same diet without CPZ. At various time points the animals were subjected to behavioral tests and their brains were analyzed. Mice exposed to CPZ for 2 and 3 weeks displayed more climbing behavior and lower prepulse inhibition, suggesting an increase in central nervous system activity and impaired sensorimotor gating. In addition, they showed lower activities of monoamine oxidase and dopamine beta hydroxylase in the hippocampus and prefrontal cortex, and had higher dopamine but lower norepinephrine levels in the prefrontal cortex. Mice exposed to CPZ for 4 to 6 weeks had less social interaction, which is an animal correlate of social withdrawal of patients with schizophrenia. Also, these CPZ-exposed mice showed evident brain demyelination, myelin break down, and loss of oligodendrocytes. At all time points the CPZ-exposed mice spent more time in the open arms of an elevated plus maze and exhibited spatial working memory impairment. These data are in line with evidence from human studies suggesting a putative role of white matter abnormality in the pathophysiology of schizophrenia.
将C57BL/6小鼠给予0.2%的铜螯合剂（CPZ），持续2至6周，而对照组食用相同但不含CPZ的饮食。在不同时间点对动物进行行为测试并分析其大脑。暴露于CPZ 2周和3周的小鼠表现出更多的攀爬行为和更低的前脉冲抑制，表明中枢神经系统活动增加且感觉运动门控受损。此外，它们在海马体和前额叶皮质中的单胺氧化酶和多巴胺β羟化酶活性较低，并且前额叶皮质中的多巴胺水平较高但去甲肾上腺素水平较低。暴露于CPZ 4至6周的小鼠社交互动较少，这是精神分裂症患者社交退缩的动物对应表现。此外，这些暴露于CPZ的小鼠表现出明显的脑脱髓鞘、髓鞘分解和少突胶质细胞丢失。在所有时间点，暴露于CPZ的小鼠在高架十字迷宫的开放臂中花费更多时间，并表现出空间工作记忆受损。这些数据与人体研究的证据一致，表明白质异常在精神分裂症的病理生理学中可能起作用。
