针刺对AD模型小鼠海马神经元突触可塑性的影响及AMPA受体机制研究
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摘要
目的：
研究针刺对阿尔兹海默病(Alzheimer's disease, AD)模型小鼠海马神经元突触可塑性及AMPA受体的影响,从AMPA受体角度探讨针刺影响神经元突触可塑性治疗AD的机制。
方法：
以Morris水迷宫为行为学检测工具,筛选学习记忆能力下降的雄性9月龄SAMP8小鼠为AD动物模型,随机分为针刺组和模型组。雄性同源同月龄SAMR1小鼠为正常对照组。
针刺“百会”、“涌泉”,每日一次,7天一疗程,疗程间间隔2天,治疗4疗程。治疗结束后,剥离脑组织。
以透射电镜观察动物海马CAl区神经元突触界面超微结构突触后致密带(post synaptic density, PSD)厚度、突触间隙宽度、突触界面曲率变化。
以蛋白质免疫印迹、免疫组织化学的方法检测海马AMPA受体亚基GluR1、 GluR2和p-GluR1、p-CaMKⅡ表达。
结果：
1.学习记忆能力基线分析结果,与对照组比较,针刺组和模型组动物Morris水迷宫定位航行实验搜索效率下降,逃避潜伏期延长(p<0.05),游泳总路程增加(p<0.05)；空间探索实验目标象限路程百分比(p<0.05)和时间百分比(p<0.05)缩小,穿越平台次数(p<0.05)和穿越有效区次数(p<0.05)减少。
2.4疗程后,与对照组比较,模型组小鼠海马CAl区神经元PSD变薄(p<0.05)；突触间隙增宽(p<0.05)；突触界面曲率下降(p<0.05)。与模型组比较,针刺组PSD增厚(p<0.05)；突触间隙宽度下降(p<0.05)；突触界面曲率增大(p<0.05)。
3.4疗程后,对照组、模型组和针刺组海马GluRl含量未见差异(p>0.05)；模型组海马CAl区GluRl含量较对照组下降(p<0.05)；针刺组呈上升趋势(p>0.05)
模型组海马GluR2,总量较对照组下降(p<0.05)；针刺组表达增强(p<0.05)。模型组海马CAl区GluR2含量较对照组下降(p<0.05)；针刺组表达增强(p<0.05)
对照组、模型组、针刺组海马p-GluRl总量未见差异(p>0.05)；模型组海马CAl区p-GluR1含量较对照组下降(p<0.05)；针刺组呈上升趋势(p>0.05)。
对照组、模型组、针刺组海马p-CaMKⅡ总量及亚区含量上均未见差异(p>0.05)。
结论：
1.10月龄SAMP8小鼠海马神经元AMPA受体病理性改变与AD相似；
2.针刺能促进AD模型小鼠海马神经元突触结构可塑性发挥；
3.调控海马神经元AMPA受体数量和亚基组成,增强突触可塑性,可能是针刺实现AD神经康复的机制之一。
Objective:
To observe the effect of AMPA receptor mediated mechanism on synaptic plasticity in hippocampal neurons of Alzheimer's disease mice enhanced by acupuncture therapy.
Methods:
The learning and memory function of9-month-old male SAMP8and SAMR1mice was assessed by using a Morris water maze(MWM) test.SAMP8mice showed poor learning and memory ability were taken as animal models of AD,and randomly divided into model group and acupuncture group.SAMR1mice with normal learning and memory ability were used as control group.
The treatment of acupuncture on DU20(Baihui) and K1(Yongquan) was applied once daily,7days as a treatment course,lasted for4courses with2days interval between courses.Mice were sacrificed after treatment,their brains were isolated.
Transmission electron microscope combining with stereological method was used to observe and measure.the synaptic ultrastructure in hippocampal neurons of CA1subregion.
Western blot and immunohistochemistry combining with image analysis were used for the quantitative and locational studies of subunits GluRl,GluR2of AMPA receptors and the phosphorylation of GluR1and CaMK II.
Results:
1. Compared to the control group, mice in acupuncture group and model group showed a poor searching efficiency (p<0.05), prolonged escaping latency (p<0.05) increased path length (p<0.05) in place navigation test(PNT),and descendent time (p<0.05) and length percentage (p<0.05) in the target quadrant,decreased site (p<0.05) and target annulus crossings (p<0.05) in spatial probe trail(SPT),witch indicated the spacial learning and memory ability of the mice in model group and acupuncture group was obviously declined.
2. In comparison to the control group, the thickness of PSD (p<0.05) and the curvature of synaptic interface (p<0.05) decreased,the width of synaptic space increased (p<0.05) in hippocampal neurons of CA1area in the model group.while the thickness of PSD (p<0.05) and the curvature of synaptic interface (p<0.05) was increased,the width of synaptic space decreased (p<0.05)
3.There were no significant differences in the total amount of GluRl in hippocampus among the three groups (p>0.05),while compared to the control group.the GluRl content in the CA1subregion in model group was declined (p<0.05),which in acupuncture group was upregulated (p>0.05)
In comparison to the control group,the GluR2quantity in hippocampus and in CA1area in model group were dicreased (p<0.05),which were upregulated in acupuncture group (p<0.05)
There were no significant differences in the total quantity of the phosphorylated GluR1and phosphorylated CaMKⅡ in hippocampus among the three groups (p>0.05).while the level of phosphorylated GluRl in the CA1subregion in model group was lower than the control group (p<0.05), which was upregulated in acupuncture group (p>0.05)
Conclusions:
1.The decrease in the number of AMPA receptor and the pathological remodeling in AMPA receptor subtype in hippocampal CA1area associated with AD provided a new neurobiology evidence for the usefulness of SAMP8as a excellent animal model for AD.
2.Acupuncture had a effect of facilitate the synaptic plasticity in hippocampal neurons of SAMP8mice.
3.Regulating the quantity and subtype of AMPA receptor in hippocampal neurons, strengthening the synaptic transmission capability,to facilitate the ability of memory acquisition and consolidation would be the therapeutic mechanism of acupuncture for AD treatment.
研究针刺对阿尔兹海默病(Alzheimer's disease, AD)模型小鼠海马神经元突触可塑性及AMPA受体的影响,从AMPA受体角度探讨针刺影响神经元突触可塑性治疗AD的机制。
方法：
以Morris水迷宫为行为学检测工具,筛选学习记忆能力下降的雄性9月龄SAMP8小鼠为AD动物模型,随机分为针刺组和模型组。雄性同源同月龄SAMR1小鼠为正常对照组。
针刺“百会”、“涌泉”,每日一次,7天一疗程,疗程间间隔2天,治疗4疗程。治疗结束后,剥离脑组织。
以透射电镜观察动物海马CAl区神经元突触界面超微结构突触后致密带(post synaptic density, PSD)厚度、突触间隙宽度、突触界面曲率变化。
以蛋白质免疫印迹、免疫组织化学的方法检测海马AMPA受体亚基GluR1、 GluR2和p-GluR1、p-CaMKⅡ表达。
结果：
1.学习记忆能力基线分析结果,与对照组比较,针刺组和模型组动物Morris水迷宫定位航行实验搜索效率下降,逃避潜伏期延长(p<0.05),游泳总路程增加(p<0.05)；空间探索实验目标象限路程百分比(p<0.05)和时间百分比(p<0.05)缩小,穿越平台次数(p<0.05)和穿越有效区次数(p<0.05)减少。
2.4疗程后,与对照组比较,模型组小鼠海马CAl区神经元PSD变薄(p<0.05)；突触间隙增宽(p<0.05)；突触界面曲率下降(p<0.05)。与模型组比较,针刺组PSD增厚(p<0.05)；突触间隙宽度下降(p<0.05)；突触界面曲率增大(p<0.05)。
3.4疗程后,对照组、模型组和针刺组海马GluRl含量未见差异(p>0.05)；模型组海马CAl区GluRl含量较对照组下降(p<0.05)；针刺组呈上升趋势(p>0.05)
模型组海马GluR2,总量较对照组下降(p<0.05)；针刺组表达增强(p<0.05)。模型组海马CAl区GluR2含量较对照组下降(p<0.05)；针刺组表达增强(p<0.05)
对照组、模型组、针刺组海马p-GluRl总量未见差异(p>0.05)；模型组海马CAl区p-GluR1含量较对照组下降(p<0.05)；针刺组呈上升趋势(p>0.05)。
对照组、模型组、针刺组海马p-CaMKⅡ总量及亚区含量上均未见差异(p>0.05)。
结论：
1.10月龄SAMP8小鼠海马神经元AMPA受体病理性改变与AD相似；
2.针刺能促进AD模型小鼠海马神经元突触结构可塑性发挥；
3.调控海马神经元AMPA受体数量和亚基组成,增强突触可塑性,可能是针刺实现AD神经康复的机制之一。
Objective:
To observe the effect of AMPA receptor mediated mechanism on synaptic plasticity in hippocampal neurons of Alzheimer's disease mice enhanced by acupuncture therapy.
Methods:
The learning and memory function of9-month-old male SAMP8and SAMR1mice was assessed by using a Morris water maze(MWM) test.SAMP8mice showed poor learning and memory ability were taken as animal models of AD,and randomly divided into model group and acupuncture group.SAMR1mice with normal learning and memory ability were used as control group.
The treatment of acupuncture on DU20(Baihui) and K1(Yongquan) was applied once daily,7days as a treatment course,lasted for4courses with2days interval between courses.Mice were sacrificed after treatment,their brains were isolated.
Transmission electron microscope combining with stereological method was used to observe and measure.the synaptic ultrastructure in hippocampal neurons of CA1subregion.
Western blot and immunohistochemistry combining with image analysis were used for the quantitative and locational studies of subunits GluRl,GluR2of AMPA receptors and the phosphorylation of GluR1and CaMK II.
Results:
1. Compared to the control group, mice in acupuncture group and model group showed a poor searching efficiency (p<0.05), prolonged escaping latency (p<0.05) increased path length (p<0.05) in place navigation test(PNT),and descendent time (p<0.05) and length percentage (p<0.05) in the target quadrant,decreased site (p<0.05) and target annulus crossings (p<0.05) in spatial probe trail(SPT),witch indicated the spacial learning and memory ability of the mice in model group and acupuncture group was obviously declined.
2. In comparison to the control group, the thickness of PSD (p<0.05) and the curvature of synaptic interface (p<0.05) decreased,the width of synaptic space increased (p<0.05) in hippocampal neurons of CA1area in the model group.while the thickness of PSD (p<0.05) and the curvature of synaptic interface (p<0.05) was increased,the width of synaptic space decreased (p<0.05)
3.There were no significant differences in the total amount of GluRl in hippocampus among the three groups (p>0.05),while compared to the control group.the GluRl content in the CA1subregion in model group was declined (p<0.05),which in acupuncture group was upregulated (p>0.05)
In comparison to the control group,the GluR2quantity in hippocampus and in CA1area in model group were dicreased (p<0.05),which were upregulated in acupuncture group (p<0.05)
There were no significant differences in the total quantity of the phosphorylated GluR1and phosphorylated CaMKⅡ in hippocampus among the three groups (p>0.05).while the level of phosphorylated GluRl in the CA1subregion in model group was lower than the control group (p<0.05), which was upregulated in acupuncture group (p>0.05)
Conclusions:
1.The decrease in the number of AMPA receptor and the pathological remodeling in AMPA receptor subtype in hippocampal CA1area associated with AD provided a new neurobiology evidence for the usefulness of SAMP8as a excellent animal model for AD.
2.Acupuncture had a effect of facilitate the synaptic plasticity in hippocampal neurons of SAMP8mice.
3.Regulating the quantity and subtype of AMPA receptor in hippocampal neurons, strengthening the synaptic transmission capability,to facilitate the ability of memory acquisition and consolidation would be the therapeutic mechanism of acupuncture for AD treatment.
引文
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