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Title: 微小兴奋性突触活动通过内源大麻受体调节抑制性突触
Author: 张思宇
Degree Level: 博士
Issued Date: 2009-10-26
Degree Grantor: 中国科学院上海生命科学研究院
Place of Degree Grantor: 上海生命科学研究院
Supervisor: 章晓辉
Keyword: 微小兴奋性突触活动 ; 抑制性突触 ; 稳态可塑性 ; 内源大麻 ; 蛋白合成 ; 真核延伸因子-2
Alternative Title: Endocannabinoid-Dependent Homeostatic Regulation of Inhibitory Synapses by Miniature Excitatory Synaptic Activities
Major: 神经生物学
Abstract: 当神经元活性受到扰动时,对突触强度进行稳态调节为保持神经环路活性的稳定发挥了重要作用。以前的工作发现,缺失微小兴奋性突触后电流(mEPSCs)数小时会引起兴奋性突触强度的上调,这提示了mEPSCs具有保持兴奋性突触(excitatory synapses)正常功能的作用。在幼年大鼠急性分离脑片的初级听皮层第二、三层的锥体神经元中,我们发现缺失mEPSCs一至三小时可以引发对抑制性突触的稳态抑制。这个稳态抑制发生在抑制性突触突触前,主要表现为微小抑制性突触后电流(mIPSCs)的频率降低而幅度不变,以及动作电位引发的抑制性突触后电流(IPSCs)的幅度降低。这个对抑制性突触的稳态调节依赖于内源大麻(endocannabinoid,eCB)信号,因为阻断eCB在中枢神经系统的受体(cannabinoid type-1 receptors,CB1Rs),或者阻断CB1R的内源配体(2-arachidonoylglycerol,2-AG)的合成都可以消除由缺失mEPSCs引起的对抑制性突触的稳态抑制。阻断I型代谢型谷氨酸受体(mGluR-I)也可以消除对抑制性突触的稳态抑制,这与以前发现的在皮层的突触中,eCB的合成和释放依赖于mGluR-I的激活是一致的。我们进一步发现,这种稳态调节还需要依赖真核延伸因子-2(eukaryotic elongation factor-2,eEF2)的蛋白合成,但并不需要基因转录。激活eEF2可以有效地降低mIPSC的频率,而这个效果可以被阻断CB1Rs消除。因此,我们的结果提示,mEPSCs对保持抑制性突触的正常功能也有重要作用;缺失mEPSCs可通过增加蛋白合成来增加eCB信号,从而引起抑制性突触的突触前抑制。
English Abstract: Homeostatic regulation of synaptic strength in response to perturbation of neuronal activity plays an important role in maintaining the overall level of neural circuit activity within a normal range. Absence of miniature excitatory postsynaptic currents (mEPSCs) for a few hours is known to cause up-regulation of excitatory synaptic strength, suggesting that mEPSCs contribute to the maintenance of excitatory synaptic functions. In the present study, we found that the absence of mEPSCs for 1-3 hr also resulted in homeostatic suppression of presynaptic functions of inhibitory synapses in acute cortical slices from juvenile rats, as suggested by the reduced frequency (but not amplitude) of miniature inhibitory postsynaptic currents (mIPSCs) as well as the reduced amplitude of IPSCs. This homeostatic regulation depended on endocannabinoid (eCB) signaling, because blockade of either the activation of cannabinoid type-1 receptors (CB1Rs) or the synthesis of its endogenous ligand 2-arachidonoylglycerol (2-AG) abolished the suppression of inhibitory synapses caused by the absence of mEPSCs. Blockade of group I metabotropic glutamate receptors (mGluR-I) also abolished the suppression of inhibitory synapses, consistent with mGluR-I requirement for eCB synthesis and release in cortical synapses. Furthermore, this homeostatic regulation also required eukaryotic elongation factor-2 (eEF2)-dependent protein synthesis, but not gene transcription. Activation of eEF2 alone was sufficient to suppress the mIPSC frequency, an effect abolished by inhibiting CB1Rs. Thus, mEPSCs contribute to the maintenance of inhibitory synaptic function and the absence of mEPSCs results in presynaptic suppression of inhibitory synapses via protein synthesis-dependent elevation of eCB signaling.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2368
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
微小兴奋性突触活动通过内源大麻受体调节抑制性突触.张思宇[d].中国科学院上海生命科学研究院,2009.20-25
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