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系統識別號 U0026-0812200914211721
論文名稱(中文) 膽紅素在海馬迴組織切片培養所誘發長期突觸塑性表現受損之作用機制探討
論文名稱(英文) Bilirubin Induces Impairment of Hippocampal Long-term Synaptic Plasticity in rat organotypic hippocampal slice cultures
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 96
學期 2
出版年 97
研究生(中文) 張芳瑀
研究生(英文) Fang-Yu Chang
電子信箱 s2695403@mail.ncku.edu.tw
學號 s2695403
學位類別 碩士
語文別 中文
論文頁數 106頁
口試委員 指導教授-許桂森
口試委員-曾淑芬
口試委員-黃阿敏
中文關鍵字 海馬迴  膽紅素 
英文關鍵字 hippocampus  bilirubin 
學科別分類
中文摘要 大部分的新生兒在出生後,由於肝臟酵素系統尚未完全發育成熟,通常會出現暫時性新生兒黃疸 (temporary physiological jaundice) 的現象。此外,有部分嬰兒則會因為膽紅素 (bilirubin) 製造過多或腸肝循環 (enterohepatic circulation) 增加而導致血漿中膽紅素過多。另外,遺傳上的差異也會使得新生兒出現黃疸的病徵。然而在嚴重的新生兒黃疸時,會導致膽紅素大量地堆積在腦中,最後演變成膽紅素腦膜炎 (bilirubin encephalopathy),對於日後成長其腦部發育上會造成很大的缺損情況。
在此研究中,我們設計一系列的研究來探討在發育中大鼠的海馬迴組織切片培養慢性處理膽紅素後,是否會改變突觸結構與其長期神經突觸塑性的表現。我們的結果發現,在發育中的海馬迴組織切片培養分別處理膽紅素 1 μM 或 10 μM 24 小時或 48 小時後會抑制海馬迴 Cornu Ammonis 1 (CA1) 區長期增益現象 (long-term potentiation, LTP) 及長期抑制現象 (long-term depression, LTD) 的表現,而且其作用方式呈現時間及劑量相關的趨勢。而膽紅素對於長期增益現象及長期抑制現象所產生的抑制,並不是因為細胞激素 (cytokines) 的釋放或神經元死亡而導致的。另外,在海馬迴組織切片培養處理膽紅素後,會降低 N-methyl D-aspartate (NMDA) 受體次單位 NR1, NR2A, NR2B 的表現。此作用可能與鈣蛋白酶 (calpain) 的活化及產生蛋白裂解 NMDA 受體次單元的作用有關。而事先投與 NMDA 受體拮抗劑或鈣蛋白酶抑制劑皆可以有效地抑制膽紅素所造成長期神經突觸塑性缺損的作用。最後我們也發現慢性膽紅素處理會減少神經樹突突觸小體的形成。總結,我們推測膽紅素影響海馬迴 CA1 區域長期突觸塑性表現的作用係透過增加 NMDA 受體的活性,其增加鈣離子的內流作用進而活化鈣蛋白酶,而導致部分 NMDA 受體次單元的裂解作用而產生的,此等發現對於了解慢性膽紅素的神經元作用有相當的助益。
英文摘要 Most human neonates experience temporary physiological jaundice, due to immaturity of hepatic conjugation and transport processes for bilirubin. However, in some infants, plasma bilirubin levels can increase dramatically owing to the excessive production or enterohepatic circulation of bilirubin, and the delayed maturation of, or inherited deficiencies in the conjugation of bilirubin. Some neonates with severe hyperbilirubinemia develop bilirubin encephalopathy, in which multifocal deposition of bilirubin in selected brain regions results in temporary or permanent impairment of brain function. In this study, we investigate whether chronic exposure of developing rat organotypic hippocampal slice cultures to unconjugated bilirubin (UCB) alters the synaptic organization and the induction of long-term synaptic plasticity. We have found that treatment of the developing rat organotypic hippocampal slice cultures to UCB 1 or 10 μM for 24 h or 48 h can impair the induction of both CA1 long-term potentiation (LTP) and long-term depression (LTD) in a time- and concentration-dependent manner. Hippocampal slice cultures stimulated with UCB showed no changes in the secretion profiles of IL-1beta and TNF-alpha or the propidium ioide (PI) uptake. UCB treatment produced a significant decrease in the levels of NR1, NR2A and NR2B subunits of NMDA receptors through a calpain-mediated proteolysis mechanism. Pretreatment of the hippocampal slice cultures with NMDA receptor antagonist or calpain inhibitors effectively prevented the UCB-induced impairment of LTP and LTD. Finally, chronic UCB treatment also decrease the number of dendrite spine in the hippocampal slice cultures. These results indicate that NMDA receptor receptor-cleavage by calpain may play critical roles in mediating the UCB-induced impairment of long-term synaptic plasticity in the developing hippocampus. We provide a significant advance in understanding the chronic effects of UCB exposure on neuronal functions.
論文目次 中文摘要 (Abstract in Chinese) II
英文摘要 (Abstract in English) V
誌謝 VII
目錄 IX
圖目錄 XII
縮寫檢索表 (Abbreviations) XV
1. 緒論 (Introduction) 2
1-1. 膽紅素 2
1-2. 新生兒黃疸與核黃疸 3
1-3. N-甲基-D-天冬氨酸受體 5
1-4. 鈣蛋白酶 6
1-5. 研究目的 8
2. 材料與方法 (Materials and Methods) 10
2-2. 藥品的來源與製備 12
2-3. 電氣生理學紀錄法 13
2-4. 西方點墨法 16
2-5. 細胞激素腫瘤壞死因子及介白素測定 24
2-6. 鈣蛋白酶活性測定 25
2-7. 細胞凋亡的偵測 25
2-8. 實時聚合酶連鎖反應 26
2-9. 腺病毒-綠色螢光蛋白感染標定神經細胞、免疫螢光染色及螢光影像分析 29
2-10. 統計分析 30
3. 實驗結果 (Results) 32
3-1. 慢性處理膽紅素對於神經突觸傳遞作用之影響 32
3-2. 慢性處理膽紅素會造成學習記憶相關的長期增益現象及長期抑制現象受損 34
3-3. 慢性處理膽紅素與細胞凋亡及細胞激素的釋放之關係 38
3-4. 慢性處理膽紅素與 NMDA 受體功能之關係 39
3-5. 慢性處理膽紅素降低 NMDA 受體次單元蛋白的表現 41
3-6. 慢性處理膽紅素所造成的 NMDA 受體次單元蛋白表現量減少的情形會被 NMDA 受體競爭性拮抗劑 D-APV 前處理所抑制 42
3-7. 慢性給予膽紅素與鈣蛋白酶活化的關係 44
3-8. 鈣蛋白酶抑制劑對於膽紅素造成神經突觸塑性與 NMDA 受體次單元蛋白表現之影響 46
3-9. 慢性膽紅素的處理對於神經結構及型態的影響 48
4. 討論 (Discussion) 51
5. 圖表 (Figures) 59
6. 參考文獻 (References) 75
7. 自述 93
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