摘要
目的:探讨脑源性神经营养因子(BDNF)/酪氨酸受体激酶B(TrkB)信号通路活性下调对孤独症大鼠模型海马神经干细胞增殖的影响及其治疗作用.方法:采用Wistar妊娠母鼠在孕期12.5d时腹腔注射丙戊酸法建立子代孤独症大鼠模型,断乳后给予侧脑室注射K252a,以下调BDNF/TrkB通路活性,应用5-溴脱氧尿嘧啶核苷(BrdU)免疫荧光观察海马神经干细胞的增殖变化,并采用水迷宫检测子代孤独症大鼠模型的学习记忆行为.结果:与对照组比较,孤独症大鼠模型海马BDNF/TrkB通路活性上升,表现为其效应分子环磷酸腺苷反应元件结合蛋白(CREB)表达显著增加,模型组海马神经干细胞增殖也显著增加;BrdU免疫荧光显色显示,K252a处理能逆转大鼠模型海马神经干细胞的过度增殖,同时,水迷宫行为学检测显示,K252a处理显著改善大鼠模型的学习记忆能力.结论:下调BDNF/TrkB通路活性可以减轻孤独症模型大鼠海马神经干细胞过度增殖并改善症状,为孤独症的临床治疗提供了实验依据.
Objective: To investigate the effects of the down-regulation of brain-derived neurotrophic factor/tyrosine receptor kinase B (BDNF/TrkB) pathway on the proliferation of neural stem cells in the hippocampus of an autistic rat model, and to further explore the concomitant therapeutic role on the behavior of the rat model. Methods: Wistar rats were exposed to valproic acid to produce autistic model at the 12.5th pregnant day in the offspring, whose BDNF/TrkB pathway in the hippocampus was downregulated by intracerebroventricular injection of K252a. The proliferation of the neural stem cells in the hippocampus, as well as the learning and memory ability of the K252a-treated autistic rat model, were tested by 5- bromodeoxyuridine (BrdU) immunofluorescent staining and Morris water maze, respectively. Results: The activity of BDNF/ TrkB pathway in the hippocampus of autistic rats, in comparison with the control, was significantly enhanced, manifesting as the increment of effector molecules, cAMP response element binding protein (CREB), BDNF/TrkB pathway. BrdU staining demonstrated that K252a, an inhibitor of BDNF/TrkB pathway, reversed the over-proliferation of neural stem cells in the hippocampus of autistic rats. Furthermore, Morris water maze test showed K252a treatment attenuated the abnormal learning and memory ability. Conclusion: Down-regulation of BDNF/TrkB pathway partly reverses the over-proliferation of neural stem cells in the hippocampus and concomitantly attenuates the abnormal behaviors of autistic rat model, thus giving experimental data for the clinical therapy of autism.
出处
《解剖学杂志》
CAS
CSCD
北大核心
2015年第2期125-128,F0002,共5页
Chinese Journal of Anatomy
基金
国家自然科学基金(81260211)
江西省自然科学基金(20114BAB205063)