精神分裂症新靶点“少突胶质细胞NMDA-R”在白质损伤中的作用及机制探讨

Schizophrenia is a severe and chronic psychiatric disorder and the etiopathogensis of schizophrenia is complicated and much unknown up to now.We recently demonstrated that the white matter damages, mainly low MBP expression and segmental demyelination or wallerian degeneration in corpus callosum, existed in the mice sub-chronic treated with MK-801, the classic schizophrenia model based on NMDA receptor antagonism. Our results indicated that the deficit of white matter was involved in the schizophrenia. Prevoius neuroimaging and postmortem studies also suggested the involvement of white matter disturbance in schizophrenia. Reduced expression of the genes associated with oligodendrocytes and myelin has also been widely discovered in schizophrenia. However, all the previous studies had the same limitation, that is, the white matter changes in schizophrenia were evaluated with the qualitative analysis methods or the semiquantitative analysis methods. In the current project, the changes of myelinated nerve fibers and the oligodentrocytes of white matter in schizophrenia were quantitatively investigated with unbiased stereological methods to overcome the limitation of previous studies. It has been shown that oligodendrocytes also express N-methyl-D-aspartate (NMDA) receptors, a new intermediary of axon to-myelin signaling. Over-activation of NMDA receptors on oligodendrocytes after ischemia could lead to excitotoxic damage of oligodendrocytes and myelin. However, the roles that the NMDA receptors on oligodendrocytes play in the schizophrenic animal model induced by NMDA receptors antagonist remains unknown. In this project, we will investigate the mechanisms of the roles that the NMDA receptors on oligodendrocytes play in the white matter changes of the schizophrenic animal model induced by NMDA antagonist and the cultured oligodendrocytes. The results will provide new theoretical evidence and novel therapeutic target for the treatment and prevention of schizophrenia.

精神分裂症是迄今为止仍未阐明发病机制的复杂疾病。苯环己哌啶（PCP）模型是目前用于精神分裂症研究最广泛的动物模型，但研究主要集中于神经元、突触及递质的异常, 忽略了占大脑总体积50%以上的白质在其中的作用。我们新近发现白质/髓鞘损伤存在于NMDA阻断剂诱导的PCP模型小鼠上，这提示白质及髓鞘损伤很可能参与了NMDA功能低下小鼠的精神分裂症发病。但大脑白质及髓鞘的损伤与精神分裂症之间到底有无关联性？白质及髓鞘形成的重要细胞少突胶质细胞在其损伤中又起什么作用？本研究拟采用新的体视学方法定量精神分裂症大脑白质及少突胶质细胞的改变，以期明确髓鞘及少突胶质细胞损伤与精神分裂症样症状之间的关系。并以参与少突胶质细胞及白质损伤的NMDA-R基因作为切入点，深入探讨少突胶质细胞NMDA-R在精神分裂症中的作用。研究结果将为精神分裂症的治疗和预防提供新信息，为精神分裂症新药开发提供新的理论依据。

精神分裂症是迄今为止仍未阐明发病机制的复杂疾病。近年来MRI/DTI等研究显示白质损伤在精神分裂症的发生发展中发挥重要作用。本研究以NMDA功能低下的精神分裂症小鼠模型和原代培养少突胶质细胞为研究对象，重点观察了NMDA阻断后模型小鼠的精神分裂症样行为学改变、白质内有髓神经纤维的脱髓鞘改变和NMDA受体亚基的表达变化。旷场实验、高架十字迷宫等行为学检测显示MK-801（NMDA受体阻断剂）处理小鼠出现自发活动增加、焦虑行为增加等精神分裂症样行为学改变；MK-801处理小鼠大脑髓鞘形成相关蛋白MBP（髓鞘碱性蛋白）、CNPase（环核苷酸-3'磷酸水解酶）的mRNA表达均低于对照小鼠的表达；MK-801处理小鼠大脑胼胝体内有髓神经纤维出现板层分离、节段性脱髓鞘等病变；体视学定量显示MK-801处理小鼠白质及胼胝体体积均低于对照小鼠，MK-801处理小鼠大脑胼胝体内有髓神经纤维总长度较对照小鼠显著降低了16.8%，主要是细小直径有髓神经纤维的丢失造成总长度的减少，这些白质损伤可能是MK-801诱导小鼠出现精神分裂症样行为改变的结构基础。MK-801处理小鼠大脑胼胝体区NMDA受体NR3A亚基表达显著高于对照组小鼠，这提示MK-801诱导的白质损伤可能通过上调少突胶质细胞NR3A亚基表达来实现，尚需体外实验进一步验证。本研究在动物水平进一步证实白质损伤在精神分裂症发生发展中的作用，并为今后髓鞘修复方面的研究提供了可能的动物模型，同时也为精神疾病的防治尤其是开发针对NMDA受体的抗精神病药物提供了新的靶点。