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系統識別號 U0026-2807201223265800
論文名稱(中文) 探討 Eps8 調控神經元結構及突觸之可塑性
論文名稱(英文) Eps8 controls structural and synaptic plasticity
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 100
學期 2
出版年 101
研究生(中文) 林昀珊
研究生(英文) Yun-Shan Lin
學號 s26994011
學位類別 碩士
語文別 中文
論文頁數 95頁
口試委員 指導教授-許桂森
口試委員-黃阿敏
口試委員-楊尚訓
中文關鍵字 結構可塑性  突觸可塑性  抑制性神經元  Eps8 基因轉殖小鼠  樹突分支複雜度  長期抑制作用 
英文關鍵字 structural and synaptic plasticity  actin dynamics  GABAergic interneurons  NMDA receptor-dependent long-term depression 
學科別分類
中文摘要 神經元的結構可塑性及突觸可塑性被廣泛的認為是神經發育過程中修飾神經聯結及成熟神經網路中執行學習及記憶等高等認知功能的重要細胞機制。 Epidermal growth factor receptor substrate 8 (Eps8) 為表皮生長因子 epidermal growth factor (EGF) 受體下游訊息傳遞路徑的細胞內受質 (substrates),能夠調節細胞骨架組成的最小單位—肌動蛋白 (actin) 的聚合。目前已知,Eps8 對於腫瘤細胞的惡化是很重要的促進性因素,其持續磷酸化會促進腫瘤細胞的增生和轉移。然而,Eps8 除了具有促進惡性腫瘤生成的角色,近年來研究發現,Eps8 基因踢除小鼠對於乙醇引起的神經元興奮作用及急性酒醉反應的副作用較具有耐受性 (tolerance),並且該小鼠小腦的顆粒細胞 (granule neurons) 的神經傳導物質受體 NMDA receptor 的活性增加,顯示 Eps8 在腦中對於神經細胞結構及突觸可塑性可能也具有重要調控角色。在本研究中,我們擬探討 Eps8 在海馬迴神經元的結構及突觸可塑性中所扮演的調控角色。主要的研究發現,在小鼠海馬迴組織中,Eps8 蛋白質在錐狀神經細胞 (pyramidal cells) 的表現量較低,而普遍表現在 cholecystokinin 或 calbindin 同時表現的抑制性神經元 (interneurons) 之細胞本體 (cell bodies) 和樹突 (dendrites)。此外,以高基染色法觀察及利用 sholl analysis 分析 Eps8 過量表現的基因轉殖小鼠 (Eps8-transgenic mice) 之海馬迴錐狀神經元的細胞結構和型態,我們發現 Eps8 基因轉殖小鼠的海馬迴 CA1 區域的錐狀神經元的樹突分支複雜度 (complexity) 增加,第一級樹突 (primary dendrites) 之突觸小棘 (dendritic spines) 密度也有明顯增加的情形。在以胞外電氣生理學實驗中,我們也發現 Eps8 基因轉殖小鼠海馬迴 CA1 區域的長期抑制作用 (long-term depression, LTD) 誘發作用受到抑制,並同時伴隨有 NMDA 受體次單元 NR1、NR2A 和 NR2B 明顯的減少,顯示 Eps8 極有可能會透過調節 NMDA 受體的表現,進而對於海馬迴神經元之突觸可塑性有重要調控作用。本研究結果對於 Eps8 蛋白質在生物體內的生理功能提供了更深入的了解,發現 Eps8 不僅僅能夠促進腫瘤細胞的增生和轉移,在腦中 Eps8 對於海馬迴神經元的結構及突觸可塑性也扮演著相當重要的調控角色。
英文摘要 Structural and synaptic plasticity are generally thought to be the cellular mechanisms underlying the refinement of neuronal connections in the developing nervous systems and contributing to the processes of learning and memory in the mature brain. Epidermal growth factor (EGF) receptor substrate 8 (Eps8) was originally cloned in a screen to isolate intracellular substrates for the kinase activity of EGF receptor, implicating in the regulation of actin dynamics. It has long been recognized that overexpression of Eps8 may lead to increased proliferation and migration of tumor cells, biological properties that are critical for tumor development and progression. Beyond its traditional role in tumorigenesis, a recent study has revealed a pivotal role of Eps8 in regulating ethanol resistance correlated with altered actin dynamics and elevated NMDA receptor activity, implying a potential role for Eps8 in the brain. Thus, the objective of this study is to investigate the role of Eps8 in regulating structural and synaptic plasticity of hippocampal neurons. Our results demonstrate that, in the hippocampus, Eps8 immunoreactivity is present at low density in pyramidal cells, but appears moderate in the cell bodies and dendrites of cholecystokinin- and calbindin-positive GABAergic interneurons. Examination of Golgi-impregnated neurons using a Sholl analysis revealed that Eps8 overexpression led to an increased amount and distribution of dendritic arbors of CA1 pyramidal neurons and dendritic spine density on long primary dendrites. In addition, Eps8 overexpression resulted in an impairment of the induction of NMDA receptor-dependent long-term depression (LTD) in the CA1 region of the hippocampus, which is correlated with a downregulation of the NMDA receptor subunits NR1, NR2A, and NR2B. Likewise, the decreased expression of NR1, NR2A, and NR2B subunits was also observed in Eps8-overexpressed hippocampal cultured neurons.Our results provide a new insight into the functional significance of Eps8 in the regulation of dendritic structure or synaptic function in hippocampal neurons, in addition to its known roles in tumorigenesis.
論文目次 第一章、 緒論 (Introduction)
1-1.Eps8 2
1-2.Eps8 在生物體內的分布和表現 2
1-3.Eps8 的蛋白結構及相關之分子作用機轉 4
1-4.神經細胞軸突及樹突生長發育 5
1-5.海馬迴神經突觸可塑性 8
1-6.海馬迴神經傳導物質和其作用受體 13
1-7.海馬迴興奮性神經元和抑制性神經元簡介 15
1-8.研究目的與假說 17
第二章、 材料與方法 (Materials and Methods)
2-1.實驗動物 22
2-2.離體大鼠海馬迴神經元培養 23
2-3.轉染 24
2-4.Eps8 基因表現重組病毒製備及離體海馬迴神經元重組病毒感 25
2-5.基因定型分析 (Genotyping) 26
2-6.西方墨點法 27
2-7.細胞膜表面蛋白之生物素標定分析(Surface biotinylation assay)33
2-8.免疫組織染色法 34
2-9.高基染色法 37
2-10.影像分析 38
2-11.海馬迴腦切片置備 39
2-12.胞外電氣生理學記錄法 40
2-13.藥物處理腦切片記錄 fEPSP 41
2-14.立體定位病毒注射法 (Setreotaxic viral injection) 42
2-15.統計分析 43
第三章、 實驗結果 (Results)
3-1.Eps8 在成年小鼠海馬迴的蛋白質表現和分布情形 45
3-2.Eps8 蛋白質在海馬迴 CA1 區域主要表現於 Schaffer collateral-associated cells 47
3-3.Eps8 基因轉殖鼠的海馬迴 CA1 區域的錐體神經細胞 (pyramidal neurons) 之樹突分支程度 (arborization) 增加及第一級樹突 (primary dendrites) 之突觸小棘 (dendritic spines) 密度增加 51
3-4.Eps8 基因轉殖鼠海馬迴之長期抑制現象 (long-term depression, LTD) 受損並伴隨有 NMDA receptor subunits 減少情形 53
第四章、 討論 (Discussion)
4-1.研究主要發現 58
4-2.海馬迴的 Eps8 蛋白質主要表現於 Schaffer collateral-associated cells 抑制性神經元 58
4-3.Eps8 對於海馬迴神經元結構可塑性之調控角色 60
4-4.Eps8 對於海馬迴神經元突觸可塑性之調控角色 63
4-5.結論 66
第五章、 圖表 68
第六章、 參考文獻 83
作者簡介
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