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目的探讨代谢性谷氨酸受体-Ⅰ(mGluR-Ⅰ)在脆性X综合征发病中的作用和mGluR-Ⅰ拮抗剂治疗的机制。方法培养FMR-1基因敲除小鼠(KO)和野生(WT)小鼠海马神经元,给予mGluR-Ⅰ激动剂和拮抗剂进行处理,Western-Blot法检测处理前后脆性X智力低下蛋白(FMRP)和微管相关蛋白1B(MAP1B),共聚焦显微镜观察树突棘的长度和密度。结果KO小鼠海马神经元树突棘长度(1·32±0·79)和MAP1B含量显著高于WT小鼠(1·00±0·62)。mGluR-Ⅰ激动剂干预后,KO和WT小鼠树突棘长度(1·60±0·88和1·33±0·80)和MAP1B均显著增加。mGluR-Ⅰ拮抗后,KO小鼠树突棘长度(0·95±0·57)和MAP1B均显著降低,在WT小鼠未见明显变化。结论脆性X综合征模型鼠由于缺乏FMRP的负性调节作用,导致mGluR-Ⅰ激活的MAP1B过度表达,可能是树突棘异常的主要原因。mGluR-Ⅰ拮抗剂逆转树突棘缺陷可能参与治疗机制。
Objective To investigate the role of mGluR-Ⅰ in the pathogenesis of fragile X syndrome and the mechanism of mGluR-Ⅰ antagonist therapy. Methods Hippocampal neurons of FMR-1 knockout (KO) mice and wild-type (WT) mice were cultured and treated with mGluR-Ⅰ agonists and antagonists. The levels of fragile X mental retardation protein (FMRP ) And microtubule-associated protein 1B (MAP1B). The length and density of dendritic spines were observed by confocal microscopy. Results The length of dendritic spine (1.32 ± 0.79) and MAP1B in hippocampal neurons of KO mice were significantly higher than those in WT mice (100 ± 0.62). After mGluR-I agonist intervention, the dendritic spine length (1.60 ± 0.88 and 1.33 ± 0.80) and MAP1B increased significantly in KO and WT mice. After mGluR-Ⅰ antagonism, the dendritic spine length (0.95 ± 0.57) and MAP1B in KO mice were significantly decreased, but no significant changes in WT mice. Conclusion Fragile X syndrome model mice lacked the negative regulatory effect of FMRP, leading to overexpression of MAP1B activated by mGluR-Ⅰ, which may be the main reason for dendritic spine abnormalities. Reversal of dendritic spine defects by mGluR-I antagonists may be involved in the therapeutic mechanism.