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组蛋白赖氨酸甲基转移酶1(EZH1)对精神分裂症诱导的社会和动机行为失调的影响
董翔廖东升赵顺成高艳红
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摘要:
目的 探讨组蛋白赖氨酸甲基转移酶(EZH)1 对精神分裂症及其导致的行为失调的影响。 方法 选择70 只C57BL/6 小鼠进行以下实验:(1)采用实时定量PCR 及Western Blot 检测小鼠各脑区及 脏器中EZH1 和EZH2 的表达。(2)小鼠给予腹腔注射3 mg/kg 的盐酸喹吡罗建立精神分裂症动物模型, 对照组给予等体积的生理盐水。给药后10 min 检测小鼠前额叶皮质(PFC)中组蛋白修饰相关蛋白的表 达。(3)分别给予小鼠腹腔注射5 mg/kg的氯氮平或0.5 mg/kg的氟哌啶醇,对照组注射等体积的生理盐水。 21 d 后检测PFC 中EZH1 和EZH2 的表达。(4)采用立体定位注射AAV-m-EZH1-shRNA 至小鼠内侧PFC 中以敲减EZH1,对照组注射干扰shRNA,2 周后检测小鼠的行为学指标。结果 (1)EZH1在小鼠的前额 叶皮质、海马、大脑皮层、皮层下、小脑和脑干等脑区中高表达,但在心脏、肾脏、肝脏、肺、胃和肠等脏 器中呈低表达。EZH2 在除小脑外的各脑区及脏器中低表达。(2)在急性注射喹吡罗后,PFC 中EZH1 的 表达显著增加(均P < 0.05),而EZH2、KDM6A、KDM6B 及UTY 的表达无显著变化(均P > 0.05)。(3)与 腹腔注射生理盐水的小鼠对比,注射氯氮平和氟哌啶醇的小鼠PFC 中EZH1 表达显著降低(均P< 0.05), 而EZH2 的表达无显著变化(P> 0.05)。(4)在社交能力测试中,EZH1 敲减可增加小鼠在陌生鼠笼的驻 留时间及对陌生鼠的嗅探时间(均P < 0.05)。在强迫游泳试验中,EZH1 敲减降低小鼠的不动时间, 增加游泳时间(均P < 0.05)。结论 EZH1 在小鼠各个脑区中高表达,在喹吡罗诱导的精神分裂症小鼠 PFC中高表达,且对抗精神病药物极敏感。EZH1 敲减可增加小鼠的社交能力,降低绝望行为。
关键词:  精神分裂症  EZH1  表观遗传调节因子  社会行为  动机行为
DOI::10.3969/j.issn.1009-6574.2019.03.008
基金项目:
Histone lysine methyltransferase( EZH) 1's effect on social and motivational behavioral disordersinduced by schizophrenia
()
Abstract:
Objectives This study focused on the effect of histone lysine methyltransferase( EZH) 1 on schizophrenia and its associated behavioral disorders. Methods Seventy C57BL/6 mice were choosen to the following four experiments.( 1)Expressions of EZH1 and EZH2 in brain regions and organs of mice were regions and organs except the cerebellum.( 2)After acute injection of quinpirole, the expression of EZH1 in PFC significantly increased( P< 0.05), while the expressions of EZH2, KDM6A, KDM6B and UTY did not significantly change( P> 0.05).( 3)Compared with mice injected with saline, the expression of EZH1 in PFC of mice injected with clozapine and haloperidol significantly decreased( P < 0.05), while the expression of EZH2 did not significantly changed( P > 0.05).( 4)In the social ability test, EZH1 knockdown increased the time for mice to spend in new cages and to sniff strange mice( P<0.05). In the forced swimming test, EZH1 knockdown reduced the immobility time of the mice and increased the swimming time in mice( P < 0.05). Conclusions EZH1 is highly expressed in various brain regions of mice, especially in PFC of quinpiroleinduced schizophrenia mice. EZH1 is extremely sensitive to antipsychotic drugs, and its knockdown increases the social ability and reduces behavioral despair of mice. detected by real-time quantitative polymerase chain reaction( PCR) and Western Blot.( 2)Mice were given an intraperitoneal injection with 3 mg/kg quinpirole hydrochloride to establish an animal model of schizophrenia, and the control group was given an equal volume of physiological saline. The expressions of histone modificationrelated proteins in the prefrontal cortex( PFC) of mice were measured at 10 min after administration(. 3)Mice were given intraperitoneal injection with 5 mg/kg of clozapine or 0.5 mg/kg of haloperidol, and the control group was injected with an equal volume of physiological saline. The expressions of EZH1 and EZH2 in PFC was measured at 21 days after injection.( 4)AAV-m-EZH1-shRNA was injected into the medial PFC of the mice to knock down EZH1, and the control group was injected with interfering shRNA. The behaviors of the mice were measured at 2 weeks after injection. Results (1)EZH1 is highly expressed in the brain regions including the prefrontal cortex, hippocampus, cerebral cortex, subcortical, cerebellum and brainstem, but is low expressed organs including the heart, kidney, liver, lung, stomach and intestines. EZH2 was low expressed in various brain
Key words:  Schizophrenia  EZH1  Epigenetic regulator  Social behavior  Motivational behavior

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