全脑缺血再灌注对海马抑制性突触功能的影响及机制
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摘要
γ-氨基丁酸(γ-Aminobutyric Acid，GABA)是中枢神经系统主要的抑制性神经递质。GABA能的抑制作用在控制正常的神经回路功能和神经元的内在放电特性，以及调控谷氨酸能突触的活动中起重要作用。GABA能系统的异常可导致神经元的高兴奋性，从而导致再灌注损伤。海马CA1区对缺血敏感，但是，缺血-再灌注如何影响海马CA1区的抑制性突触功能，目前还不清楚。本文围绕海马与缺血-再灌注，应用电生理和免疫组织化学技术手段探讨了缺血-再灌注对海马抑制性突触功能的影响，并对其作用机制进行了研究。
第一部分全脑缺血-再灌注对海马CA1区抑制性突触功能的影响
目的观察全脑缺血-再灌注对海马CA1区抑制性突触功能的影响。方法成年雄性SD大鼠，体重200-250g，随机分为5组：(1)假手术组(sham)；(2)缺血再灌注12小时组(is12h)；(3)缺血再灌注24小时组(is24h)；(4)缺血再灌注3天组(is3d)和(5)缺血再灌注7天组(is7d)共5组。用四动脉阻断法制作全脑缺血模型(10min)，使用全细胞电压钳技术记录海马脑片CA1区锥体细胞的抑制性突触后电流(Inhibitory Postsynaptic Currents，IPSCs)。结果is12h组自发性抑制性突触后电流(Spontaneous Inhibitory Postsynaptic Currents，sIPSCs)和miniature抑制性突触后电流(miniature Inhibitory Postsynaptic Currents，mIPSCs)的频率明显降低，但sIPSCs和诱发性抑制性突触后电流(evoked Inhibitory Postsynaptic Currents，eIPSCs)的下降时间却明显延长。而且，GABA转运体抑制剂NO-711可使假手术组eIPSCs的下降时间明显延长，却不能使is12h组eIPSCs的下降时间进一步延长；再灌注24小时，IPSCs的频率和下降时间恢复正常；再灌注3天，sIPSCs和mIPSCs的频率明显增加，但IPSCs的幅值和动力学没有影响；再灌注7天，sIPSCs和mIPSCs的频率恢复正常，但sIPSCs的幅值降低，而mIPSCs的幅值却没有明显改变。结论全脑缺血-再灌注后，海马CA1区抑制性突触功能呈现动态变化，在再灌注损伤中起重要作用。
为了进一步明确全脑缺血-再灌注后海马CA1区抑制性突触功能变化的机制，我们又进行了第二部分实验。
第二部分全脑缺血-再灌注对海马CA1区GAD-65和GAT-1表达的影响及意义
目的探讨全脑缺血-再灌注对成年大鼠海马CA1区谷氨酸脱羧酶(glutamicacid decarboxylase，GAD)同工酶GAD-65和γ-氨基丁酸转运体1(γ-AminobutyricAcid transport-1，GAT-1)表达的影响及意义。方法成年雄性SD大鼠，体重200-250g，随机分为5组：(1)假手术组(sham)；(2)缺血再灌注12小时组(is12h)；(3)缺血再灌注24小时组(is24h)；(4)缺血再灌注3天组(is3d)和(5)缺血再灌注7天组(is7d)共5组。用四动脉阻断法制作全脑缺血模型(10min)，应用免疫组织化学方法检测海马CAI区GAD-65和GAT-1的表达。结果与假手术组相比，is3d组GAD-65的表达明显增多；is12h组GAT-1的表达明显减少。结论GABA能中间神经元对缺血相对耐受，并且全脑缺血-再灌注12小时GAT-1表达的减少和再灌注3天GAD-65表达的增加可能都是机体的一种代偿机制，通过增强抑制性突触功能来减轻再灌注后的兴奋毒性。
从以上两部分实验可以看出，GABA介导的抑制性突触功能在缺血-再灌注中起重要作用。再灌注12小时，突触前GABA能中间神经元的功能异常导致了缺血-再灌注损伤。再灌注3天，GABA能的增强可能是通过GAD-65的表达增多来实现的。但是，再灌注7天抑制性突触功能的降低可能是通过突触后的机制实现的。此外，再灌注12小时GAT-1表达的减少导致了IPSCs下降时间的延长。因此，再灌注12小时GAT-1表达的减少和再灌注3天GAD-65表达的增多可能都是代偿性的机制，通过增强抑制性突触功能来降低缺血后的兴奋毒性。
γ- Aminobutyric Acid(GABA) is the main inhibitory neurotransmitter in the CNS. Moreover, GABAergic inhibition plays a critical role in controlling normal circuit function, regulating the intrinsic burst-firing properties of neurons, and modulating the activation of glutamatergic synapses. Impairment in the GABAergic system can lead to neuronal hyperexcitability which contributes to ischemia-reperfusion injury. Although hippocampal CA1 area is one of the regions most sensitive to ischemic challenge, the effects of global cerebral ischemia-reperfusion on inhibitory synaptic function in hippocampal CA1 area of adult rats are still unclear. In this study, we investigated inhibitory synaptic function in hippocampal CA1 area of adult rats following global ischemia-reperfusion using electrophysiological and imrnunohistochemical techniques.
Part one The effect of global ischemia-reperfusion on inhibitory synaptic function in hippocampal CA1 region
Objective To observe the effects of global ischemia-reperfusion on inhibitory synaptic function in hippocampal CA1 region of adult rats. Methods All animals were randomly divided into five groups: sham-operation group (SH), ischemia-reperfusion 12 hours (is12h), ischemia-reperfusion 24 hours(is24h),ischemia-reperfusion 3 day (is3d) and ischemia-reperfusion 7 day (is7d) groups. Global Ischemic episode was achieved by 4-vessel occlusion for 10min. Inhibitory postsynaptic currents (IPSCs) were recorded from CA1 pyramidal cells in slices using whole-cell voltage-clamp. Results 12 hours after ischemia-reperfusion (is12h), spontaneous IPSCs and miniature IPSCs were less frequent but the decay-time constant for evoked and spontaneous IPSCs were significantly increased than in sham group. Furthermore, GABA transport inhibitors NO-711 prolonged evoked IPSC decay constant of sham CA1 pyramidal cells but had no effect on is12h neurons. 24 hours after ischemia-reperfusion (is24h), the frequency, amplitude, and the kinetics of IPSCs were normal. However, 3 days after ischemia-reperfusion (is3d), the spontaneous IPSCs and miniature IPSCs frequency were higher compared with sham rats. 7 days after ischemia-reperfusion (is7d), spontaneous IPSCs were smaller in amplitude than in sham rats. However, the amplitude, frequency, and the kinetics of miniature IPSCs were normal. Conclusion Our findings suggest that alteration of inhibitory synaptic function in hippocampal CA1 area of adult rats may play an important role in ischemia-reperfusion injury.
Part two The effect of global ischemia-reperfusion on the expression of GAD65 and GAT-1 in hippocampal CA1 region
Objective In order to examine the possible mechanisms of alteration of inhibitory synaptic function in hippocampal CA1 area after ischemia-reperfusion injury, we further do the second part of the experiment to investigate the expression of GAD-65 (glutamic acid decarboxylase 65, GAD-65) and GABA transporter 1 (GAT-1) in hippocampal CA1 area after global cerebral ischemia-reperfusion. Methods All animals were randomly divided into five groups: sham-operation group (SH), ischemia-reperfusion 12 hours (is12h), ischemia-reperfusion 24 hours(is24h), ischemia-reperfusion 3 day (is3d) and ischemia-reperfusion 7 day (is7d) groups. Global Ischemic episode was achieved by 4-vessel occlusion for 10min. ImmunohistochemiCA1 method was applied to observe the expression of GAD65 and GAT-1 in hippocampal CA1 region. Results ImmunohistochemiCA1 staining for GAT-1 and GAD-65 revealed a reduction in GABA transporter 1 (GAT-1) expression 12 hours after ischemia-reperfusion (is12h), and an enhancement of GAD-65 expression 3 days after ischemia-reperfusion (is3d).But, the expression of GAT-1 and GAD-65 in hippocampal CA1 area at 24 hours (is24h) and 7 days (is7d) after ischemia-reperfusion was similar to that of sham rats. Conclusion These results suggest that GABAergic interneurons were relatively resistant to ischemia-reperfusion injury. Furthermore, the decreased expression of GAT-1 12 hours after ischemia-reperfusion, and the elevated expression of GAD-65 3 days after ischemia-reperfusion could be the compensatory mechanisms to reduce the hyperexcitability associated with ischemia-reperfusion.
These results suggest that alterations in GABA-mediated synaptic inhibition play an essential role after ischemia-reperfusion. 12 hours after ischemia-reperfusion, it is the dysfunction of presynaptic GABAergic interneurons contributes to the ischemia-reperfusion injury. 3 days after ischemia-reperfusion, the enhancement in GABAergic function could due to the increased expression of GAD-65. However, 7 days after ischemia-reperfusion, it is likely that postsynaptic alteration contributes to the reduced inhibition. Furthermore, the decreased expression of GAT-1 prolonged decay-time constant 12 hours after ischemia-reperfusion.Therefore, both the decreased GAT-1 expression 12 hours after ischemia-reperfusion and increased GAD-65 expression 3 days after ischemia-reperfusion could be compensatory mechanisms to reduce the hyperexcitability associated with ischemia-reperfusion.
第一部分全脑缺血-再灌注对海马CA1区抑制性突触功能的影响
目的观察全脑缺血-再灌注对海马CA1区抑制性突触功能的影响。方法成年雄性SD大鼠，体重200-250g，随机分为5组：(1)假手术组(sham)；(2)缺血再灌注12小时组(is12h)；(3)缺血再灌注24小时组(is24h)；(4)缺血再灌注3天组(is3d)和(5)缺血再灌注7天组(is7d)共5组。用四动脉阻断法制作全脑缺血模型(10min)，使用全细胞电压钳技术记录海马脑片CA1区锥体细胞的抑制性突触后电流(Inhibitory Postsynaptic Currents，IPSCs)。结果is12h组自发性抑制性突触后电流(Spontaneous Inhibitory Postsynaptic Currents，sIPSCs)和miniature抑制性突触后电流(miniature Inhibitory Postsynaptic Currents，mIPSCs)的频率明显降低，但sIPSCs和诱发性抑制性突触后电流(evoked Inhibitory Postsynaptic Currents，eIPSCs)的下降时间却明显延长。而且，GABA转运体抑制剂NO-711可使假手术组eIPSCs的下降时间明显延长，却不能使is12h组eIPSCs的下降时间进一步延长；再灌注24小时，IPSCs的频率和下降时间恢复正常；再灌注3天，sIPSCs和mIPSCs的频率明显增加，但IPSCs的幅值和动力学没有影响；再灌注7天，sIPSCs和mIPSCs的频率恢复正常，但sIPSCs的幅值降低，而mIPSCs的幅值却没有明显改变。结论全脑缺血-再灌注后，海马CA1区抑制性突触功能呈现动态变化，在再灌注损伤中起重要作用。
为了进一步明确全脑缺血-再灌注后海马CA1区抑制性突触功能变化的机制，我们又进行了第二部分实验。
第二部分全脑缺血-再灌注对海马CA1区GAD-65和GAT-1表达的影响及意义
目的探讨全脑缺血-再灌注对成年大鼠海马CA1区谷氨酸脱羧酶(glutamicacid decarboxylase，GAD)同工酶GAD-65和γ-氨基丁酸转运体1(γ-AminobutyricAcid transport-1，GAT-1)表达的影响及意义。方法成年雄性SD大鼠，体重200-250g，随机分为5组：(1)假手术组(sham)；(2)缺血再灌注12小时组(is12h)；(3)缺血再灌注24小时组(is24h)；(4)缺血再灌注3天组(is3d)和(5)缺血再灌注7天组(is7d)共5组。用四动脉阻断法制作全脑缺血模型(10min)，应用免疫组织化学方法检测海马CAI区GAD-65和GAT-1的表达。结果与假手术组相比，is3d组GAD-65的表达明显增多；is12h组GAT-1的表达明显减少。结论GABA能中间神经元对缺血相对耐受，并且全脑缺血-再灌注12小时GAT-1表达的减少和再灌注3天GAD-65表达的增加可能都是机体的一种代偿机制，通过增强抑制性突触功能来减轻再灌注后的兴奋毒性。
从以上两部分实验可以看出，GABA介导的抑制性突触功能在缺血-再灌注中起重要作用。再灌注12小时，突触前GABA能中间神经元的功能异常导致了缺血-再灌注损伤。再灌注3天，GABA能的增强可能是通过GAD-65的表达增多来实现的。但是，再灌注7天抑制性突触功能的降低可能是通过突触后的机制实现的。此外，再灌注12小时GAT-1表达的减少导致了IPSCs下降时间的延长。因此，再灌注12小时GAT-1表达的减少和再灌注3天GAD-65表达的增多可能都是代偿性的机制，通过增强抑制性突触功能来降低缺血后的兴奋毒性。
γ- Aminobutyric Acid(GABA) is the main inhibitory neurotransmitter in the CNS. Moreover, GABAergic inhibition plays a critical role in controlling normal circuit function, regulating the intrinsic burst-firing properties of neurons, and modulating the activation of glutamatergic synapses. Impairment in the GABAergic system can lead to neuronal hyperexcitability which contributes to ischemia-reperfusion injury. Although hippocampal CA1 area is one of the regions most sensitive to ischemic challenge, the effects of global cerebral ischemia-reperfusion on inhibitory synaptic function in hippocampal CA1 area of adult rats are still unclear. In this study, we investigated inhibitory synaptic function in hippocampal CA1 area of adult rats following global ischemia-reperfusion using electrophysiological and imrnunohistochemical techniques.
Part one The effect of global ischemia-reperfusion on inhibitory synaptic function in hippocampal CA1 region
Objective To observe the effects of global ischemia-reperfusion on inhibitory synaptic function in hippocampal CA1 region of adult rats. Methods All animals were randomly divided into five groups: sham-operation group (SH), ischemia-reperfusion 12 hours (is12h), ischemia-reperfusion 24 hours(is24h),ischemia-reperfusion 3 day (is3d) and ischemia-reperfusion 7 day (is7d) groups. Global Ischemic episode was achieved by 4-vessel occlusion for 10min. Inhibitory postsynaptic currents (IPSCs) were recorded from CA1 pyramidal cells in slices using whole-cell voltage-clamp. Results 12 hours after ischemia-reperfusion (is12h), spontaneous IPSCs and miniature IPSCs were less frequent but the decay-time constant for evoked and spontaneous IPSCs were significantly increased than in sham group. Furthermore, GABA transport inhibitors NO-711 prolonged evoked IPSC decay constant of sham CA1 pyramidal cells but had no effect on is12h neurons. 24 hours after ischemia-reperfusion (is24h), the frequency, amplitude, and the kinetics of IPSCs were normal. However, 3 days after ischemia-reperfusion (is3d), the spontaneous IPSCs and miniature IPSCs frequency were higher compared with sham rats. 7 days after ischemia-reperfusion (is7d), spontaneous IPSCs were smaller in amplitude than in sham rats. However, the amplitude, frequency, and the kinetics of miniature IPSCs were normal. Conclusion Our findings suggest that alteration of inhibitory synaptic function in hippocampal CA1 area of adult rats may play an important role in ischemia-reperfusion injury.
Part two The effect of global ischemia-reperfusion on the expression of GAD65 and GAT-1 in hippocampal CA1 region
Objective In order to examine the possible mechanisms of alteration of inhibitory synaptic function in hippocampal CA1 area after ischemia-reperfusion injury, we further do the second part of the experiment to investigate the expression of GAD-65 (glutamic acid decarboxylase 65, GAD-65) and GABA transporter 1 (GAT-1) in hippocampal CA1 area after global cerebral ischemia-reperfusion. Methods All animals were randomly divided into five groups: sham-operation group (SH), ischemia-reperfusion 12 hours (is12h), ischemia-reperfusion 24 hours(is24h), ischemia-reperfusion 3 day (is3d) and ischemia-reperfusion 7 day (is7d) groups. Global Ischemic episode was achieved by 4-vessel occlusion for 10min. ImmunohistochemiCA1 method was applied to observe the expression of GAD65 and GAT-1 in hippocampal CA1 region. Results ImmunohistochemiCA1 staining for GAT-1 and GAD-65 revealed a reduction in GABA transporter 1 (GAT-1) expression 12 hours after ischemia-reperfusion (is12h), and an enhancement of GAD-65 expression 3 days after ischemia-reperfusion (is3d).But, the expression of GAT-1 and GAD-65 in hippocampal CA1 area at 24 hours (is24h) and 7 days (is7d) after ischemia-reperfusion was similar to that of sham rats. Conclusion These results suggest that GABAergic interneurons were relatively resistant to ischemia-reperfusion injury. Furthermore, the decreased expression of GAT-1 12 hours after ischemia-reperfusion, and the elevated expression of GAD-65 3 days after ischemia-reperfusion could be the compensatory mechanisms to reduce the hyperexcitability associated with ischemia-reperfusion.
These results suggest that alterations in GABA-mediated synaptic inhibition play an essential role after ischemia-reperfusion. 12 hours after ischemia-reperfusion, it is the dysfunction of presynaptic GABAergic interneurons contributes to the ischemia-reperfusion injury. 3 days after ischemia-reperfusion, the enhancement in GABAergic function could due to the increased expression of GAD-65. However, 7 days after ischemia-reperfusion, it is likely that postsynaptic alteration contributes to the reduced inhibition. Furthermore, the decreased expression of GAT-1 prolonged decay-time constant 12 hours after ischemia-reperfusion.Therefore, both the decreased GAT-1 expression 12 hours after ischemia-reperfusion and increased GAD-65 expression 3 days after ischemia-reperfusion could be compensatory mechanisms to reduce the hyperexcitability associated with ischemia-reperfusion.
引文
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