慢性不可预见性应激大鼠海马NMDA受体与kalirin和NOS表达的关系
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摘要
抑郁症是由各种原因所引起的以心境低落,思维迟钝,语言行动减少为主要特征的心境障碍或情感性障碍。随着日常压力增大,抑郁症发病率也呈逐年上升的趋势,且具有高发病率、高复发率、发病年龄逐年降低等特点。抑郁症的发生与社会环境、心理、神经生化和遗传等多方面因素有关,但抑郁症确切的病因及病理机制尚不清楚。海马是目前抑郁症研究中涉及最多的脑区。最近的研究表明兴奋性氨基酸与抑郁症的发病过程有着密切的关系,海马谷氨酸及其受体介导的兴奋性毒性在许多精神心理障碍的发生中发挥关键作用。我们的研究通过慢性不可预见性温和应激(chronic unexpected mild stress,CUMS)抑郁模型,探讨应激性抑郁发生与NMDA受体,以及NMDA受体与神经可塑性改变的关系,实验选取成年雄性SD大鼠,建立慢性不可预见性应激抑郁模型,并通过海马微量注射相关药物(MK-801和N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)),采用体重测量(Body weight measurement)、糖水偏爱测试(Scurose preference test,SPT)、强迫游泳(Forced swimming test,FST)及敞箱实验(Open field test,OFT)等方法检测动物行为,运用免疫组织化学方法检测海马内一氧化氮合酶(nitric oxide synthase,NOS)包括神经元型NOS与诱导型NOS,和kalirin的表达变化,探索抑郁症的发生机制。研究结果如下:
1.CUMS组大鼠表现出抑郁样行为变化:21天实验阶段中,对照组大鼠体重变化呈明显上升趋势,而CUMS组体重增长不明显,与对照组相比,体重变化率在第7、14、21天均有极显著性差异(p＜0.01);经过慢性不可预见性应激的大鼠糖水消耗量明显低于应激前(p＜0.01),对糖水的偏爱也显著低于对照组(p＜0.05);CUMS组敞箱实验的水平运动和垂直运动得分都明显低于对照组(p＜0.01),修饰得分也显著低于对照组(p＜0.05);进行了21天的CUMS后大鼠的FST不动时间明显高于对照组(p＜0.05)。
2.海马微量注射NMDA,动物行为学表现与CUMS组相似,与对照组相比,也出现体重增长缓慢,糖水消耗降低,敞箱得分降低和FST不动时间增高的现象;海马微量注射非竞争性NMDA受体拮抗剂MK-801能明显改善应激引起的抑郁样行为表现,各项行为测试结果都有向正常水平恢复的趋势。
3.慢性不可预见性温和应激模型大鼠海马nNOS与iNOS的表达与对照组相比均有极显著性升高(p＜0.01),而kalirin在海马的表达出现极显著下降(p＜0.01)。MK-801+CUMS组与CUMS组相比海马齿状回与CA3区nNOS的表达均有极显著性下降(p＜0.01),CA3区iNOS的表达显著下降(p＜0.05),kalirin表达显著上升(p＜0.01);NMDA组海马齿状回nNOS表达与对照组相比显著升高(p＜0.05),iNOS在海马的表达与对照组相比有极显著性升高(p＜0.01),而kalirin表达有极显著的降低(p＜0.01)。
由以上结果可以看出,CUMS能够引起大鼠抑郁样行为特征,即动物快感缺乏,兴趣丧失,体重降低,生理活动迟缓及行为绝望等表现。CUMS能够引起大鼠抑郁样行为特征,并引起大鼠海马NOS高表达,而kalirin表达下降。海马注射NMDA受体激动剂能够有效的产生与CUMS相似的抑郁样行为症状,且引起与应激相似的NOS的高表达,kalirin表达下降。而CUMS导致的抑郁样行为表现又可以通过海马微量注射NMDA受体的阻断剂来改善,起到了抗抑郁样作用,同时,微量注射NMDA受体的阻断剂使得海马NOS表达下降,kalirin表达升高。由此可见,慢性不可预见性应激引起海马NMDA受体过度激活,海马kalirin表达下降,NOS高表达,产生过量的NO,造成海马神经元损伤,可能是导致抑郁样行为发生的重要机制之一。
Depression is associated with significant morbidity and functional disability, and it is thus important to reveal the mechanism of depression. The hippocampus has recently attracted tremendous attention for the study of depression. A variety of studies suggest an involvement of glutamic acid (Glu)and N-methyl-D-aspartic acid (NMDA) receptor in the pathophysiological mechanism of depression development. Since accumulated evidence indicates a role of nitric oxide (NO) in brain impairment produced by chronic stress. Chronic stress can increase expression of nitric oxide synthase (NOS) in hippocampus, and stimulate NO release may be involved in development of depression. It is unknown, however, whether the relationship of NMDA receptor and NOS also makes contributions to the mechanism of Chronic Stress-induced depression, and the behavioural ability of the rodents. Kalirin is necessary for maintenance of dendritic spines and dendritic branches. Previous research revealed that the atrophy of dendrities could be induced by chronic stress or ovariectomy, but that whether Kalirin is involved in the pathology of chronic stress-induced depression through influencing the changes of dendrities, and the relationship between NMDAR and kalirin is not known until recently.
This study show that intra-hippocampal injections of the NMDA receptor agonist (N-methyl-D-aspartic acid), and antagonist MK-801 during chronic unexpected mild stress (CUMS) affect behavioral changes including body weight, sucrose preference, locomotor activity, rearing and grooming in open field test, and duration of immobility in forced swimming test. The expression of neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) and kalirin in rat hippocampus also were observed by immunohistochemistry.
Rats receiving CUMS for 21 days display a variety of behavioral measures of depression, including a significant reduction in body weight, sucrose preference, and locomotion, rearing and grooming in open field test, and a significant increase in immobility time in forced swimming test, and the expression of nNOS and iNOS increased and expression of kalirin decreased in hippocampus. The behavioral ability of the intra-hippocampal injections of NMDA receptor agonist rats dramatically depressed and the expression of nNOS in dental gyrus (DG) increased, the expression of iNOS increased in both DG and CA3 area of hippocampus, the expression of kalirin significantly reduction. Intra-hippocampal injection of noncompetitive NMDA antagonist MK-801 significantly prevent CUMS-induced depression-like behavioral changes, decreased the expression of nNOS in both DG and CA3 area and the expression of iNOS in CA3 area, and significant increase in that of kalirin-IR cells in hippocampus.
Both CUMS and intra-hippocampal injections of NMDA receptor agonist can induce depression-like behavioral changes, increased the expression of NOS and reduction in the expression of kalirin in hippocampus. NMDA receptor antagonist decreased the expression of NOS, suppressed CUMS-induced depression-like behavioral changes. This study provide the evidence suggesting that CUMS which results in development of depression may induce neurotoxicity in hippocampal neurons by stimulating Glu release, inducing excessively activation of NMDA receptor, reducing expression of kalirin, increasing expression of NOS, and influence the neural plasticity in CNS.
1.CUMS组大鼠表现出抑郁样行为变化:21天实验阶段中,对照组大鼠体重变化呈明显上升趋势,而CUMS组体重增长不明显,与对照组相比,体重变化率在第7、14、21天均有极显著性差异(p＜0.01);经过慢性不可预见性应激的大鼠糖水消耗量明显低于应激前(p＜0.01),对糖水的偏爱也显著低于对照组(p＜0.05);CUMS组敞箱实验的水平运动和垂直运动得分都明显低于对照组(p＜0.01),修饰得分也显著低于对照组(p＜0.05);进行了21天的CUMS后大鼠的FST不动时间明显高于对照组(p＜0.05)。
2.海马微量注射NMDA,动物行为学表现与CUMS组相似,与对照组相比,也出现体重增长缓慢,糖水消耗降低,敞箱得分降低和FST不动时间增高的现象;海马微量注射非竞争性NMDA受体拮抗剂MK-801能明显改善应激引起的抑郁样行为表现,各项行为测试结果都有向正常水平恢复的趋势。
3.慢性不可预见性温和应激模型大鼠海马nNOS与iNOS的表达与对照组相比均有极显著性升高(p＜0.01),而kalirin在海马的表达出现极显著下降(p＜0.01)。MK-801+CUMS组与CUMS组相比海马齿状回与CA3区nNOS的表达均有极显著性下降(p＜0.01),CA3区iNOS的表达显著下降(p＜0.05),kalirin表达显著上升(p＜0.01);NMDA组海马齿状回nNOS表达与对照组相比显著升高(p＜0.05),iNOS在海马的表达与对照组相比有极显著性升高(p＜0.01),而kalirin表达有极显著的降低(p＜0.01)。
由以上结果可以看出,CUMS能够引起大鼠抑郁样行为特征,即动物快感缺乏,兴趣丧失,体重降低,生理活动迟缓及行为绝望等表现。CUMS能够引起大鼠抑郁样行为特征,并引起大鼠海马NOS高表达,而kalirin表达下降。海马注射NMDA受体激动剂能够有效的产生与CUMS相似的抑郁样行为症状,且引起与应激相似的NOS的高表达,kalirin表达下降。而CUMS导致的抑郁样行为表现又可以通过海马微量注射NMDA受体的阻断剂来改善,起到了抗抑郁样作用,同时,微量注射NMDA受体的阻断剂使得海马NOS表达下降,kalirin表达升高。由此可见,慢性不可预见性应激引起海马NMDA受体过度激活,海马kalirin表达下降,NOS高表达,产生过量的NO,造成海马神经元损伤,可能是导致抑郁样行为发生的重要机制之一。
Depression is associated with significant morbidity and functional disability, and it is thus important to reveal the mechanism of depression. The hippocampus has recently attracted tremendous attention for the study of depression. A variety of studies suggest an involvement of glutamic acid (Glu)and N-methyl-D-aspartic acid (NMDA) receptor in the pathophysiological mechanism of depression development. Since accumulated evidence indicates a role of nitric oxide (NO) in brain impairment produced by chronic stress. Chronic stress can increase expression of nitric oxide synthase (NOS) in hippocampus, and stimulate NO release may be involved in development of depression. It is unknown, however, whether the relationship of NMDA receptor and NOS also makes contributions to the mechanism of Chronic Stress-induced depression, and the behavioural ability of the rodents. Kalirin is necessary for maintenance of dendritic spines and dendritic branches. Previous research revealed that the atrophy of dendrities could be induced by chronic stress or ovariectomy, but that whether Kalirin is involved in the pathology of chronic stress-induced depression through influencing the changes of dendrities, and the relationship between NMDAR and kalirin is not known until recently.
This study show that intra-hippocampal injections of the NMDA receptor agonist (N-methyl-D-aspartic acid), and antagonist MK-801 during chronic unexpected mild stress (CUMS) affect behavioral changes including body weight, sucrose preference, locomotor activity, rearing and grooming in open field test, and duration of immobility in forced swimming test. The expression of neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) and kalirin in rat hippocampus also were observed by immunohistochemistry.
Rats receiving CUMS for 21 days display a variety of behavioral measures of depression, including a significant reduction in body weight, sucrose preference, and locomotion, rearing and grooming in open field test, and a significant increase in immobility time in forced swimming test, and the expression of nNOS and iNOS increased and expression of kalirin decreased in hippocampus. The behavioral ability of the intra-hippocampal injections of NMDA receptor agonist rats dramatically depressed and the expression of nNOS in dental gyrus (DG) increased, the expression of iNOS increased in both DG and CA3 area of hippocampus, the expression of kalirin significantly reduction. Intra-hippocampal injection of noncompetitive NMDA antagonist MK-801 significantly prevent CUMS-induced depression-like behavioral changes, decreased the expression of nNOS in both DG and CA3 area and the expression of iNOS in CA3 area, and significant increase in that of kalirin-IR cells in hippocampus.
Both CUMS and intra-hippocampal injections of NMDA receptor agonist can induce depression-like behavioral changes, increased the expression of NOS and reduction in the expression of kalirin in hippocampus. NMDA receptor antagonist decreased the expression of NOS, suppressed CUMS-induced depression-like behavioral changes. This study provide the evidence suggesting that CUMS which results in development of depression may induce neurotoxicity in hippocampal neurons by stimulating Glu release, inducing excessively activation of NMDA receptor, reducing expression of kalirin, increasing expression of NOS, and influence the neural plasticity in CNS.
引文
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