MK-801诱导的精神分裂症小鼠行为学和胼胝体髓鞘的改变

摘要

Objective To explore the role of white matter injuries in the schizophrenia induced by the NMDA re-ceptor antagonist. Methods Adult male C57BL/6J mice (8 week old) were equally divided into four groups. One group was sub-chronically treated with saline solution, and the other three groups were intraperitoneally treated with MK-801 at dose of 0.025 mg/mL (M1), 0.050 mg/mL (M2) and 0.100 mg/mL (M3) in a volume 10 ml per kilogram body weight. All ani-mals were tested using Morris water maze at the 9th-15th day and using the Hole Board exploration as well as Rota Rod performance tests on the 16th day. The myelin basic protein (MBP) and the ultrastructure of the myelin sheaths in the cor-pus callosum were then examined using immunohistochemical methods, transmission electron microscope technique and stereological methods. Results The repeated sub-chronic MK-801 treatment did not induce impairment of spatial learning and memory in Morris water maze. The MK-801 treatment at 0.25 mg/kg and 1.00 mg/kg but not at 0.50 mg/kg resulted in less exploration to a new environment. The myelin staining with anti-MBP antibody was less intense in all three schizo-phrenic groups when compared to saline control group (P<0.01). Furthermore, MK-801 treatment caused pathological al-terations of the myelin sheaths including segmental demyelination of myelinated fibers and splitting of myelin sheath lamel- lae in schizophrenic groups. The ratio of the injured myelinated nerve fibers in the corpus callosum of MK-801 treated mice [M3 group, (22.42 ± 4.24)%] was significantly higher when compared to the control mice [(3.84 ± 1.35)%,P<0.01)]. Conclusions The present study demonstrated the white matter damages, mainly low MBP expression and segmental demye-lization in the corpus callosum in the mice sub-chronic treated with MK-801, indicating that the white matter changes might be involved in the schizophrenia induced by NMDA antagonist.%目的：探讨白质/髓鞘损伤在N-甲基-D-天冬氨酸（N-methyl-D aspartate，NMDA）受体阻断致精神分裂症（schizophrenia，SZ）中的作用。方法雄性C57 BL/6J小鼠（8周龄）48只，随机分为地卓西平马来酸盐（dizocilpine, MK-801)慢性给药M1组（0.25mg/kg）、M2组（0.50mg/kg）和M3组（1.00mg/kg）及对照组（生理盐水）。以Morris水迷宫、探孔和转棒测试检验小鼠行为学改变，运用免疫组化、透射电镜及体视学方法观察其胼胝体内髓鞘的改变。结果各模型组小鼠与对照组比较，空间学习记忆能力无明显下降（均P>0.05），M1和M3组小鼠较对照组表现出对新环境探索减少的SZ阴性症状；大脑胼胝体区MBP染色M1组（179±10）%、M2组（235±7）%、M3组（152±9）%小鼠较对照组（288±18）%均降低（均P<0.01），其内有髓神经纤维髓鞘出现板层分离、节段性脱髓鞘等病变，M3组小鼠胼胝体内损伤有髓神经纤维比例高于对照组[（22.42±4.24）%vs.（3.84±1.35）%]，差异有统计学意义（P<0.01）。结论胼胝体脱髓鞘改变可能是MK-801慢性给药诱导SZ的病因之一。