ω-3PUFAs调控CREB/BDNF/TrkB信号传导通路对精神分裂症认知功能损伤的防治作用及机制研究

Schizophrenia (SZ) has cognitive impairment. The level of BDNF that participates in learning and memory is decreased in SZ brain, while omega-3PUFAs could improve SZ symptoms, but the mechanism of how they intervene SZ is unknown. Applicants have found that supplementation of omega-3PUFAs can (1)increase the levels of p-CREB, BDNF and p-TrkB in brain of SZ rats, (2) restore the number of hippocampal neurons, (3) reduce cognitive impairment in SZ rats. We hypothesize that omega-3PUFAs may mediate SZ cognitive impairment by upregulating the CREB / BDNF / TrkB pathway. The project intends to: (1) detect CREB / BDNF / TrkB pathway and behavioral changes by MK801 in FAT-1 transgenic rats (overexpression of omega-3PUFAs) and control rats to investigate the effect of omega-3PUFAs mediate BDNF pathway on the interference of SZ cognitive function. (2) The patients with SZ from 18 to 65 years of age are enrolled in this study who are randomized to receive either placebo or omega-3PUFAs, Plasma BDNF levels were measured and the SZ symptoms were evaluated by the scale to study the relationship between SZ symptoms and up-regulation of BDNF by omega-3PUFAs. Through clinical studies to confirm the hypothesis, which can provide new clues for the occurrence of SZ cognitive impairment mechanism and provide a clinical basis for its prevention and treatment .

SZ存在认知障碍；参与学习记忆的BDNF水平在SZ脑中降低；ω-3PUFAs可改善SZ症状，但二者干预SZ的机制不明。申请人发现：补充ω-3PUFAs①可升高SZ小鼠脑内p-CREB、BDNF、p-TrkB水平；②恢复海马神经元数目；③减轻SZ小鼠认知功能损伤。我们推测：ω-3PUFAs可能通过上调CREB/BDNF/TrkB通路干预SZ认知障碍。本项目拟①应用MK801于FAT-1转基因小鼠（过表达ω-3PUFAs）和对照小鼠，检测CREB/BDNF/TrkB通路和行为学变化，明确ω-3PUFAs介导BDNF通路对SZ认知功能损伤的影响；②以18至65岁SZ患者为研究对象，分组接受安慰剂或ω-3PUFAs，检测血浆BDNF水平，应用量表评价SZ认知功能，分析ω-3PUFAs上调BDNF与SZ认知恢复的关系，在临床研究证实假说，为SZ认知障碍的发生机制提供新线索，为其防治提供临床研究基础。

精神分裂症是一种严重的精神疾病，与认知障碍有关。脑源性神经营养因子（BDNF）是中枢神经系统中发现的一种学习和记忆相关分子，据报道其水平在精神分裂症患者脑中降低，而ω-3多不饱和脂肪酸（ω-3PUFAs）可改善精神分裂症症状，但其作用机制尚不清楚。通过MK801注射诱导的精神分裂症大鼠模型，我们发现补充ω-3PUFAs可提高精神分裂症大鼠大脑中p-CREB、BDNF和p-TrkB的水平，恢复海马神经元损伤，从而减少精神分裂症大鼠的认知障碍。然而，过表达AAV9/CREB S133A（CREB失活突变）下调了BDNF/TrkB信号通路，并显著消除了ω-3PUFAs对MK801诱导的精神分裂症的预防作用。而AAV9/CREB S133D（CREB激活突变）改善了MK801大鼠的突触功能障碍和认知缺陷。这些发现表明，MK801诱导的精神分裂症病变使CREB在Ser133部位去磷酸化，导致神经元损伤，而ω-3PUFAs通过诱导CREB Ser133磷酸化来调控CREB/BDNF/TrkB通路，从而激活CREB，增加突触可塑性，减少海马神经元丢失，从而拮抗MK801诱导的大鼠精神分裂症认知功能障碍，改善精神分裂症的认知损伤。在临床试验中我们发现4g/d的ω-3PUFAs可以提升精神分裂症患者血浆中HDL的水平，提高精神分裂症患者红细胞膜中DHA和EPA的比例，同时可以增强精神分裂症患者的信息处理速度，在一定程度上改善患者的认知。本研究为MK801诱导的精神分裂症记忆和认知障碍的分子机制提供了基础，并通过临床试验验证ω-3PUFAs可以增强精神分裂症患者的信息处理速度，为ω-3PUFAs治疗和预防精神分裂症提供了思路。