重复经颅磁刺激对精神分裂症小鼠模型认知 功能及海马内源性大麻素基因表达的影响
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国家自然科学基金项目(81904280,81630032,81671343)


Impact of rTMS on cognitive function and endocannabinoid-related gene expression in the hippocampus in mice model of schizophrenia
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    摘要:

    目的 探讨重复经颅磁刺激(rTMS)对双环己酮草酰二腙(CPZ)诱导的精神分裂症小鼠认 知损伤的改善作用及内源性大麻素受体 1(CB1R)、二酰基甘油脂肪酶(DAGLα)、N 酰基磷脂酰乙醇胺 磷脂酶 D(NAPE-PLD)、脂肪酰胺水解酶(FAAH)和单酰基甘油脂肪酶(MAGL)表达的影响。方法 将 24 只 C57BL/6 小鼠随机分为对照组(sham)、模型组(CPZ)、模型 +rTMS 治疗组(CPZ+rTMS),每组 8 只。 CPZ+rTMS 组和 CPZ 组小鼠饲喂含有 0.2% CPZ 的饲料 6 周后,分别接受 7 d 的 rTMS(5 Hz,1.26 Tesla)或 假刺激;sham 组正常饲喂 6 周并接受 7 d 的 rTMS 假刺激。最后一次 rTMS 干预结束 24 h 后进行 Y 迷宫和 三箱社交测试;随后处死动物,取海马组织进行蛋白质印迹实验,检测其内源性大麻素相关基因的蛋白 表达变化。结果 与 sham 组相比,CPZ 组表现出明显的空间记忆损伤和社交缺陷,包括 Y 迷宫实际交 替进臂百分比下降[sham 组(62.69±7.92)% 比 CPZ 组(43.78±14.30)%,P< 0.01]和三箱社交实验中与 2 处陌生小鼠接触时间减少[sham 组(233.41±3.84)比(157.02±63.62)s,P< 0.05;CPZ 组(164.30±79.16) 比(249.28±58.31) s,P< 0.05]。与 sham 组小鼠相比,CPZ 组小鼠海马的 CB1R、DAGLα 和 NAPE-PLD 蛋白表达下调[(1.14±0.09)比(0.77±0.13)、(0.76±0.12)比(0.38±0.10)、(0.81±0.12)比(0.36±0.11),P< 0.05],而 FAAH 表达上调[(0.73±0.09)比(1.14±0.16),P< 0.05]。rTMS 干预可以改善 CPZ 小鼠的空间 记忆损伤和社交缺陷,CPZ+rTMS 组小鼠在 Y 迷宫测试中的实际交替进臂百分比较 CPZ 组上调[CPZ 组 (43.78±14.30)% 比 CPZ+rTMS 组(60.40±10.62)%,P< 0.05)];三箱社交实验中,CPZ+rTMS 组小鼠与 2 处 陌生小鼠接触时间更长[(236.74±51.66)比(158.41±68.45) s,P<0.05]。rTMS干预可以恢复CPZ小鼠海 马的内源性大麻素相关基因表达水平,CPZ+rTMS 组小鼠海马的 CB1R、DAGLα、FAAH 和 NAPE-PLD 蛋 白水平[(1.13±0.11)、(0.68±0.13)、(0.66±0.08)、(0.64±0.14)]与 CPZ 组比较,差异均有统计学意义(P< 0.05)。结论 rTMS 可以改善 CPZ 诱导的精神分裂症小鼠模型的认知损伤并调节该小鼠海马内源性大 麻素相关基因表达水平。

    Abstract:

    Objective To investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on cognitive impairment and the expression of endocannabinoid system-related genes, including CB1R (cannabinoid receptor1), DAGLα (Diacylglycerol-α), NAPE-PLD (N acylphosphatidyl ethanolamine phospholipase D), FAAH (Fatty acid amide hydrolase) and MAGL (monoacylglycerol) in the hippocampus in cuprizone (CPZ)-induced mice model of schizophrenia. Methods A total of 24 C57BL/6 mice were randomly assigned to the following 3 groups (n=8 for each group): sham, CPZ and CPZ + rTMS. The mice in the CPZ + rTMS and CPZ group were administered 0.2% CPZ in standard powdered rodent chow for 6 weeks, then received rTMS treatment (5 Hz, 1.26T) or sham rTMS treatment for 7 days; concurrently, the mice in sham group were fed with normal powdered rodent chow for 6 weeks, and then received sham rTMS treatment for 7 days. 24 hours after the completion of the last rTMS intervention, mice were subjected to Y-maze and 3-chamber tests. Then the mice were sacrificed, and Western blot was used to detect the protein expression of cannabinoid related genes in hippocampus. Results Compared with sham group, CPZ group showed significant spatial memory impairment and social deficits, including decreased percentages of spontaneous alternations in Y maze test [sham (62.69±7.92)% vs CPZ (43.78±14.30)%, P < 0.01], and less duration with stranger in the 3-chamber test [sham: (233.41±3.84) vs (157.02±63.62), P<0.05); CPZ: (164.30±79.16) vs (249.28±58.31) s,P< 0.05)]. Compared with sham group, the expression levels of CB1R, DAGLα and NAPE-PLD in hippocampus of the CPZ group was decreased [(1.14±0.09) vs (0.77±0.13), (0.76±0.12) vs (0.38±0.10), (0.81±0.12) vs (0.36±0.11), P < 0.05], while expression of FAAH of the CPZ group was increased [(0.73±0.09) vs (1.14±0.16), P < 0.05]. rTMS treatment improved cognitive impairment and social deficits in mice exposed to CPZ, evidenced by increased percentages of spontaneous alternations in Y maze test in CPZ+rTMS group than in CPZ group [CPZ: (43.78±14.30)% vs CPZ+rTMS: (60.40±10.62)%, P< 0.05], and more duration with stranger in the 3-chamber test [(236.74±51.66) vs (158.41±68.45) s, P< 0.05]. rTMS treatment reversed the level of endocannabinoid system-related genes in the hippocampus of CPZ mice, since the differences of the expression levels of CB1R, DAGLα and NAPE-PLD in hippocampus between CPZ+rTMS group [(1.13±0.11), (0.68±0.13), (0.66±0.08), (0.64±0.14)] and CPZ group were statistically significant (P < 0.05). Conclusions rTMS treatment can improve the cognitive impairment in CPZ-induced schizophrenia mice model and restored the protein level of endocannabinoid system-related genes in the hippocampus.

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于欢 薛姗姗 赵建帅 王莹 赵洁玉 谭庆荣 周翠红.重复经颅磁刺激对精神分裂症小鼠模型认知 功能及海马内源性大麻素基因表达的影响[J].神经疾病与精神卫生,2021,21(8):
DOI :10.3969/j. issn.1009-6574.2021.08.001.

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  • 在线发布日期: 2021-08-31