喹硫平和槟榔碱治疗精神分裂症脑髓鞘异常的分子机理

Clinic and animal studies have shown that there is myelin dysfunction in the brain of schizophrenia. In order to clarify whether myelin dysfunction is the cause or result of schizophrenia, we proposed the phencyclidine-induced neurodevelopmental schizophrenia rat model, and will investigate myelin dysfunction at different stages of schizophrenia and determine the role of myelin dysfunction in schizophrenia-like behavior. Meantime, whether antipsychotic quetiapine and myelin-protective arecoline are able to target myelin dysfunction and attenuate schizophrenia-like behavior, will also be investigated to determine the role of myelin abnormalities in the pathogenesis of schizophrenia. The project will employ a multidimensional approach to investigate the myelin dysfunction mechanism in schizophrenia. Firstly, the project will demonstrate the therapeutic effect of quetiapine and arecoline in the treatment of schizophrenia rats by measuring animal behavior; secondly, it will reveal that the therapeutic effect of quetiapine and arecoline in schizophrenia is related to their regulation mechanism on myelin abnormalities through brain-derived neurotrophic factor signaling pathway in rat frontal cortex by molecular cell biology and whole transcriptome sequencing measurement; finally, the project will furtherly show myelin abnormalities in frontal cortex play an important role in the neurologic loop of schizophrenia by using optogenetic and electrophysiological methods. The above expected results of this project will help to clarify (1): the role of myelin dysfunction in the pathogenesis of schizophrenia; (2): the value of targeting myelin abnormalities in frontal cortex as a potential therapeutic target for future schizophrenia drug development.

临床和动物模型研究显示精神分裂症脑内存在着髓鞘异常。为验证脑髓鞘异常是否是精神分裂症的发病机制中的关键因素之一，并能否可作为精神分裂症的治疗新靶点，本项目将在课题组前期工作基础上探讨抗精神病药喹硫平和髓鞘保护药槟榔碱对苯环利定所致神经发育障碍大鼠模型精神分裂样行为的治疗作用以及与调节脑髓鞘异常相关治疗机制。本项目首先采用行为学方法确认喹硫平和槟榔碱对大鼠精神分裂症样行为治疗的有效性；其次利用分子细胞学和全转录组测序方法检测鼠脑前皮质细胞结构、蛋白及转录因子揭示喹硫平和槟榔碱对精神分裂症的治疗与其通过脑源性生长因子信号通路对髓鞘异常的调控机制相关；最后采用光遗传和电生理学等方法揭示鼠脑前皮质髓鞘异常在引发精神分裂症神经环路中起重要作用。上述本项目预期结果有助于阐明（1）：与脑髓鞘功能障碍相关的精神分裂症发病机制；（2）：脑前皮质髓鞘异常可作为精神分裂症的治疗新靶点。

本研究分别探讨了喹硫平和槟榔碱对精神分裂症模型鼠的行为学改善作用及其潜在的保护髓鞘的机制，氟西汀改善精神分裂症模型鼠感觉运动门控缺陷的机制，糖原合成酶激酶-3β (glycogen synthase kinase-3 beta , GSK3β) 基因多态性在精神分裂症人群和正常人群中的差异以及对阿立哌唑血药浓度的影响。研究结果表明，喹硫平能够改善MK-801精神分裂症模型鼠的自发活动、空间记忆能力以及感觉门控功能，显著促进小鼠额叶皮层中MBP和BDNF的表达；槟榔碱能够改善小鼠的空间记忆能力，抑制Cuprizone诱导的高自主性活动，缓解抑郁症状，促进MBP、CNPase、GSTpi和PDGFR等髓鞘相关蛋白的表达；氟西汀能够缓解MK-801诱导的精神分裂症模型鼠的感觉运动门控缺陷，促进前额皮质内BDNF的表达水平；GSK3β基因rs6438552、rs12630592、rs3732361位点与精神分裂症易感性相关，可能影响阿立哌唑的血药浓度。通过本项目的开展，我们发现喹硫平和槟榔碱对精神分裂症的治疗作用可能与其对脑髓鞘的神经保护作用有关，喹硫平和氟西汀可能通过调控BDNF信号通路而发挥其髓鞘保护作用，这表明脑髓鞘可能是精神分裂症的一个新的治疗靶点；GSK3β基因多态性研究结果可以为阿立哌唑的临床用药提供指导，对于提高阿立哌唑的治疗效果也具有重要的临床意义。