特异性干扰肽对海马突触可塑性的影响及其功能研究
文献类型：学位论文
| 作者 | 吴坤 |
| 学位类别 | 硕士 |
| 答辩日期 | 2009-06 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 徐林 |
| 关键词 | 海马 长时程增强 长时程抑制 AMPA受体 条件化位置偏爱的表达 |
| 中文摘要 | 在哺乳动物复杂的神经网络中，突触是信息传递的枢纽，其突触传递效能的持续性变化被称为突触可塑性（synaptic plasticity）。长时程增强（long-term potentiation，LTP）和长时程抑制（long-term depression，LTD）现象是两种经典的突触可塑性形式，被视作学习和记忆可能的物质基础，得到了广泛地关注。其中，海马CA1区谷氨酸能突触处的LTP和LTD目前研究得最为广泛。 α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid（AMPA）受体作为介导兴奋性谷氨酸能突触基础传递的主要受体，是海马CA1区LTP和LTD正常表达的必要条件。近期的研究表明，AMPA受体通过胞吞、胞吐及侧向移动等方式在细胞膜和细胞内进行着持续地循环。因此，通过调节AMPA受体的上、下膜，进而影响突触后膜上AMPA受体的数量，便能对LTP和LTD产生影响。在本研究中，我们利用生物信息学的手段，以AMPA受体为靶点，设计出了旨在特异阻断LTP或LTD的多肽。运用离体脑片全细胞记录方式，在海马CA1区证明了干扰肽Pep-A2能够特异地阻断LTP而不影响LTD，Pep-A3能够特异地阻断LTD而不影响LTP。并初步探究了其关键的作用位点，为进一步理解LTP和LTD具体的分子机理打下了基础。成瘾作为异常的学习记忆过程，势必涉及到突触可塑性的变化。而特异性地阻断LTP和LTD，对药物成瘾效果的影响却鲜有报道（Wang YT，2007）。在另一部分工作中，我们采用穿膜肽Tat-A2和Tat-A3，在吗啡条件化位置偏爱（morphine conditioned place preference，morphine CPP）模型小鼠的测试前进行系统给药，结果发现两种干扰肽均能阻断或损伤其CPP的表达过程。这一现象，提示我们LTP和LTD在条件化位置偏爱的表达过程中都是不可或缺的，同时也为人们更好地理解成瘾过程的机理，及开发专一有效的治疗药物提供了新的思路。 |
| 英文摘要 | In the mammalian neural network, synapses are the connection sites of information transfer between neurons. Changes in synaptic strength, called synaptic plasticity, in the form of long-term potentiation (LTP) and long-term depression (LTD), is generally believed to be the cellular mechanism underlying learning and memory. And now, LTP and LTD of excitatory glutamatergic synapses around pyramidal neurons of area CA1, has been studied extensively. α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, as the major receptors to mediate synaptic transmission of excitatory glutamatergic synapses, are necessary for the expression of LTP and LTD. Recent studies have demonstrated that AMPA receptors are continuously recycled between plasma membrane and intra-cellular by means of exocytosis, endocytosis and lateral diffusion. Therefore, regulation of AMPA receptors trafficking results in a rapid change in the number of AMPA receptors on the postsynaptic membrane, then influencing on the expression of either LTP or LTD. In our study, peptides targeted on AMPA receptors have been synthesized by bioinformatics to block LTP/LTD. Using blind whole-cell recordings from CA1 pyramidal neurons in acute hippocampal slice, we find that intracellular application of Pep-A2 can specifically interfere with LTP rather than LTD, and Pep-A3 can specifically affect LTD but not LTP. Also a preliminary investigation of the crucial sites has been carried on, thereby providing a foundation for further studies on the mechanisms of LTP and LTD. Drug addiction, as a pathological learning and memory, is involved with modulation of synaptic plasticity. However, there are few reports on the effect of drug addiction by inhibiting LTP/LTD respectively（Wang YT，2007）. In another study, we find that Tat-A2/Tat-A3 can impair the expression of morphine induced conditioned place preference (CPP), with systemically treating the mice with the Tat-peptides before the test phases of the CPP paradigm. This result suggests that both LTP and LTD are necessary for the expression of morphine CPP. Meantime, it helps us further understand the mechanisms of drug addiction and develop effective medicine. |
| 语种 | 中文 |
| 公开日期 | 2010-10-22 |
| 源URL | [http://159.226.149.42:8088/handle/152453/6308]  |
| 专题 | 昆明动物研究所_学习记忆的分子神经机制 |
| 推荐引用方式 GB/T 7714 | 吴坤. 特异性干扰肽对海马突触可塑性的影响及其功能研究[D]. 北京. 中国科学院研究生院. 2009. |
入库方式： OAI收割
来源：昆明动物研究所
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