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系統識別號 U0026-0812200913475178
論文名稱(中文) 探討PI3K徑路在急性壓力所導致海馬廻長期突觸塑性改變所扮演的角色
論文名稱(英文) study of the role of phosphatidylinositol 3-kinase signaling pathway in the stress-induced modification of hippocampal long-term 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 95
學期 2
出版年 96
研究生(中文) 楊秉鈞
研究生(英文) Ping-chun Yang
學號 s2694403
學位類別 碩士
語文別 中文
論文頁數 125頁
口試委員 指導教授-許桂森
口試委員-黃阿敏
口試委員-郭余民
中文關鍵字 海馬迴  長期增益現象  長期抑制作用  急性壓力 
英文關鍵字 PI3K  hippocampus  LTP  LTD  PSD-95 
學科別分類
中文摘要 壓力會影響海馬廻神經元長期突觸塑性的表現,雖然我們實驗室過去的研究已經證實活化BDNF/Ras/MARK徑路可能參與此調控作用的發生,但是否有其他訊息傳遞徑路參與其中,則仍然不清楚。先前的文獻指出phosphatidylinositol-3 kinase (PI3K)徑路對於神經細胞的存活及調控神經突觸長期增益現象表現上扮演著重要的角色,因此我們想進一步的探討PI3K徑路是否也參與急性壓力所導致海馬廻長期神經突觸塑性(如長期增益現象和長期抑制作用)改變的分子機制中。我們主要發現給予大鼠急性壓力(restraint and electric shock)會明顯地增加PI3K在海馬廻CA1的活性(以Akt磷酸化的程度表示),同時也發現,若抑制PI3K徑路可以阻斷急性壓力對於長期增益現象和長期抑制作用改變的作用。腹腔給予醣皮質固醇受體抑制劑(RU38486)或於海馬廻CA1區域局部投予PI3K抑制劑(如LY294002或wortmannin)、N-methyl-D-aspartate (NMDA)受體競爭性拮抗劑(DL-2-amino-5-phosphonopentanoic acid, APV)、tyrosine receptor kinase B (TrkB)受體抑制劑(K252a),以及側腦室投予brain-derived neurotrophic factor (BDNF)反義股寡核酸序列,皆可抑制急性壓力引起的PI3K活化,顯示急性壓力引起PI3K的活化需要這些上游的訊息分子的參與。經由西方點墨法的分析顯示,在海馬廻CA1區域中,急性壓力會明顯地活化PI3K下游之PDK1-Akt-mTOR-p706K-eIF4B徑路。此外,抑制mTOR徑路也可以阻斷急性壓力對於長期增益現象和長期抑制作用改變。給予大鼠急性壓力會增加海馬廻CA1區域中postsynaptic density-95 (PSD-95)的表現。此外若分離突觸神經小體(synaptoneurosome)後,亦發現PSD-95的表現增加,並且受到PI3K-mTOR徑路的活化所調控。這些發現顯示突觸神經小體中PSD-95的增加是透過局部蛋白質轉譯作用的調控作用。我們也研究發現急性壓力後會導致海馬廻CA1區域之NR2B次體磷酸化的作用受到抑制。綜合以上的結果,我們發現PI3K徑路在海馬廻CA1區域中嶄新的生理角色:其具有調控急性壓力所引起的神經長期突觸塑性改變。
英文摘要 Stress has been shown to dramatically affect the induction of hippocampal synaptic plasticity; however, the molecular details of how it does so remain unclear. Although phosphatidylinositol-3 kinase (PI3K) signaling plays a crucial role in promoting neuronal survival and neuroplasticity, but its role, if any, in stress-induced alterations of LTP or LTD is unknown. We firstly found here that inhibitors of PI3K signaling blocked the effect of stress on LTP and LTD. Therefore, the purpose of the present study is to elucidate the signaling events involving PI3K in terms of its role in mediating stress-induced alterations of LTP and LTD. We found that stress-induced PI3K activation can be blocked by various inhibitors including RU38486 for glucocorticoid receptors, LY294002 for PI3K, DL-2-amino-5-phosphonopentanoic acid for NMDA receptors, K252a for tyrosine kinase receptors, or BDNF antisense oligonucleotides. Also, immunoblotting analyses revealed that stress induced a profound and prolonged phosphorylation of a number of PI3K downstream effectors, including 3-phosphoinositide-dependent protein kinase-1 (PDK1), protein kinase B, mammalian target of rapamycin (mTOR), p70S6 kinase and eukaryotic initiation factor 4B (eIF4B) in hippocampal CA1 homogenates, which were prevented by the PI3K inhibitor pretreatment. More importantly, we found that stress significantly increased the protein expression of dendritic scaffolding protein postsynaptic density-95, which is known to involve in LTP and LTD, in an mTOR-dependent manner. These results identify a key role of PI3K signaling in mediating the stress-induced modification of hippocampal synaptic plasticity and further suggest that PI3K may do so by invoking the protein expression of PSD95.
論文目次 頁數
中文摘要 01
英文摘要 04
縮寫檢索表 06
第一章 緒論 09
第二章 材料與方法 43
一、實驗動物 44
二、動物急性壓力模式 44
三、動物埋管投藥模式 45
四、海馬廻腦薄片的製備 48
五、電氣生理學記錄法 49
六、西方點墨法與免疫沉澱法 50
七、突觸神經小體物質的分離 58
八、BDNF濃度測定 59
九、免疫組織螢光染色法 59
十、統計分析 61
第三章 實驗結果 62
第四章 討論 81
第五章 圖表 90
第六章 參考文獻 106
圖表索引 124
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