臺灣博碩士論文加值系統

中文摘要
新生兒缺氧是造成新生兒腦部傷害的主要原因之一，會造成新生兒終其一生具毀滅性的神經功能障礙後遺症，如增加日後發生癲癇發作之危險性以及有關學習與記憶執行力的損害。突觸後緻密結構蛋白質(PSD) 是一種細胞支架的特殊結構，位於中樞神經興奮性突觸後膜之下。PSD密切參與控制突觸功能與調節突觸後神經，是一種對興奮性刺激反應的動態性結構。 PSD-95以PDZ區域結合受體蛋白質C端四個胺基酸來聯結N-甲基-D-天門冬胺酸(NMDA)受體的NR2A與NR2B次單元，因而活化了NMDA受體媒介的反應物質，如學習及記憶相關之轉錄因子-磷酸化的環腺苷酸反應單元結合蛋白 (pCREBSerine-133）。
本論文之目的主要是研究新生鼠缺氧環境所誘發出日後抽搐感受性增加以及有關學習與記憶執行力損害的大白鼠，其中樞海馬回及大腦皮質神經細胞PSD-95、NMDA受體次單元和pCREBSerine-133的蛋白質質體表現所受到的影響，並且探討是否經由活化多巴胺D1/D5受體可以影響這些蛋白質質體的表現以及上述研究目標是否伴隨成鼠抽搐發生機率之降低以及有關學習與記憶執行力的改善。
本論文之第一部分，在成鼠(P45)時施與pentylenetetrazol (PTZ)之注射以誘發抽搐，用於評估抽搐感受性之病變可能性。論文之第二部分，利用水迷宮試驗來探討實驗動物有關學習與記憶執行力損害的情形。本論文並應用免疫組織化學染色法、共軛免疫沈澱法及西方墨點技術來探討抽搐感受性增加以及有關學習與記憶執行力損害的大白鼠，在成鼠(P45)時其三個代表性腦區(海馬迴CA1區、中腦和顳葉皮質)的神經細胞損傷的情形，以及PSD-95、NMDAR次單元(NR1、NR2A 和NR2B)和pCREBSerine-133的蛋白質質體表現之改變情況。論文並進一步評估活化多巴胺D1/D5受體對實驗動物之療效。
本論文之結果顯示抽搐感受性增加以及有關學習與記憶執行力損害的大白鼠，在成鼠(P45)時其神經細胞損傷的腦區,主要是在中腦，而不在顳葉皮質和海馬迴CA1區。然而，pCREBSerine-133蛋白質質體表現的降低，在三個代表性腦區都可以觀察得到。新生鼠缺氧亦導致中腦和海馬迴CA1區(顳葉皮質除外)的PSD-95蛋白質質體表現降低; 此外，共軛免疫沈澱法及西方墨點技術也顯示PSD-95和NMDA受體次單元的蛋白質質體表現明顯地被週產期缺氧所改變。此外，本論文顯示，在P17-24以可通透中樞神經之選擇性致效劑A68930(2mg/kg)活化多巴胺D1/D5受體途徑，不僅能改善水迷宮試驗的認知執行力，而且能提升PSD-95/NMDA受體的表現及其下游訊息CREBserine-133的磷酸化能力。
綜合以上結果顯示抽搐感受性增加以及有關學習與記憶執行力損害的大白鼠，其PSD-95和NMDA受體次單元分子間的動態連接能力可被在新生鼠時的缺氧所改變。另外， PSD-95以及pCREBSerine-133的蛋白質質體的表現降低亦呈現區域性差異(spatial-preferential difference)，進而參與新生兒腦部缺氧病變的形成，例如增加抽搐感受性以及有關學習與記憶執行力損害的細胞機轉基礎。更重要的是，於新生兒缺氧後，活化多巴胺D1/D5受體有意義地減輕長期神經缺陷，顯示此種訊息途徑的有利活動，可能對新生兒缺氧引發腦病變提供有用之治療策略。

英文摘要
Perinatal hypoxia is an important cause of brain injury in the newborn and has consequences that are potentially devastating and life-long, such as increased risks of epilepsy and impaired performance as regards learning and memory in later life for the affected individual. The postsynaptic density (PSD) is a cytoskeletal specialization involved in the anchoring of neurotransmitter receptors and in regulating the response of postsynaptic neurons to synaptic stimulation. The postsynaptic protein PSD-95 binds to the N-methyl-D-aspartate receptor (NMDAR) subunit, and hence activates cascades of NMDAR-mediated events, such as cyclic adenosine monophosphate (cAMP)-responsive element binding protein phosphorylation at serine-133 (pCREBSerine-133).
Here we studied the effect of perinatal hypoxia on protein interactions involving PSD-95 and the NMDAR, as well as pCREBSerine-133 expression at an age when the animals show increased seizure susceptibility and impaired performance as regards learning and memory. We also assessed the therapeutic efficacy of dopamine D1/D5 receptor (D1/D5R) activation for such study animals.
Rats were assigned randomly to the control rats or the rats exposed to transient global hypoxia on postnatal day 10 (P10). The first part of this study have focused on the seizure susceptibility for the affected individual treated with pentylenetetrazol (PTZ) intraperitoneally on P45. In the second part of this study, the water maze test was applied to the test animals following earlier experimentation . We analyzed the levels of neuronal loss, pCREBSerine-133, PSD-95, and NMDAR expressions in the midbrain, temporal cortex, and hippocampal CA1 subfield by using immunohistochemistry, co-immunoprecipitation, and immunoblotting techniques, respectively. We also assessed the therapeutic efficacy of dopamine D1/D5 receptor (D1/D5R) activation for such study animals.
The rats with prior exposure to perinatal hypoxia exhibited increased seizure susceptibility to PTZ and impaired performance as regards learning and memory in later life, compared with the control rats. Associated with this long-term change in seizure susceptibility and in impaired performance as regards learning and memory in later life, selective neuronal loss was observed in the midbrain region while pCREBSerine-133 expression was reduced in the midbrain, temporal cortex, and hippocampal CA1 subfield. Perinatal hypoxia led to a decrease in PSD-95 expression in the both midbrain and hippocampal CA1 subfield, with the exception of temporal cortex. Furthermore, the association between PSD-95 and NMDAR subunits (NR1, NR2A, and NR2B) in the hippocampal CA1 was also markedly altered by perinatal hypoxia. In addition, activation of the D1/D5R via A68930 (a selective, CNS-permeable agonist of D1/D5Rs) administration (2 mg/kg/day, P17–23 inclusively) markedly attenuated the hypoxia-induced deleterious effects, suggesting an effective therapeutic efficacy for A68930.
This study demonstrates that the decrease in several protein complexes that are essential components of the postsynaptic apparatus is associated with the observed increase in seizure susceptibility and an increased risk of impaired performance as regards learning and memory in later life for the affected individual. The results indicate that reductions in PSD-95 expression, PSD-95 binding of NMDAR subunits, and subsequent NMDAR-mediated CREB phosphorylation, particularly in hippocampal CA1, are long-term consequences of perinatal hypoxia and may, at least in part, contribute to perinatal hypoxia-induced increased risks of epilepsy and impaired performance as regards learning and memory. More importantly, D1/D5R activation following perinatal hypoxia may be an alternative therapeutic strategy to that which is currently available and may offer significant clinical potential for hypoxia
sufferers.

目錄
正文目錄……………………………………………………………..Ⅱ
圖目錄………………………………………………………………..Ⅳ
英文縮寫……………………………………………………………..Ⅴ
附錄目錄……………………………………………………………..Ⅶ
中文摘要……………………………………………………………..Ⅷ
英文摘要……………………………………………………………..XI















正文目錄
第一章、緒言
第一節、新生兒之腦部發育與缺氧反應……………………..2
第二節、N-甲基-D-天門冬胺酸受體…………………………3
第三節、突觸後緻密結構 ……………………………………4
第四節、缺氧對NMDA受體和PSD-95的影響…………….6
第五節、學習及記憶相關之轉錄因子………………………...7
第六節、本論文研究的目的…………………………………...9
第二章、材料與方法
第一節、實驗動物……………………………………………..11
第二節、動物模式之建立: 誘導缺氧反應…………………...11
第三節、抽搐感受性…………………………………………..12
第四節、水迷宮試驗…………………………………………..12
第五節、免疫組織化學染色法………………………………...13
第六節、腦組織切片之製備 ………………………………….14
第七節、共軛免疫沈澱法及西方墨點技術……………………16
第八節、數據分析………………………………………………17
第三章、探討新生鼠缺氧所引發腦部PSD-95/NMDA受體複合物及長期抽搐感受性之改變
第一節、實驗模式之背景 ……………………………………..19
第二節、實驗步驟………………………………………………22
第三節、實驗結果………………………………………………24
第四節、討論……………………………………………………32
第五節、後記……………………………………………………36
第四章、新生鼠缺氧引發海馬迴CA1區突觸後緻密結構蛋白質質體表現的改變
第一節、實驗模式之背景 ……………………………………..37
第二節、實驗步驟………………………………………………38
第三節、實驗結果………………………………………………42
第四節、討論……………………………………………………50
第五節、後記……………………………………………………55
第五章、結論與展望…………………………………………………56
參考文獻………………………………………………………………57
附錄……………………………………………………………………65








圖目錄
第三章之圖目錄
圖1、為實驗設計之圖解摘要………………………………………23
圖2、新生鼠缺氧後長期之腦組織切片結果………………………27
圖3、P45時 Neu-N免疫組織化學染色細胞總數………………...28
圖4、缺氧對三個腦區之PSD-95長期(P45)表現的效應………....29
圖5、缺氧對三個腦區之pCREBSerine-133長期(P45)表現的效應….30
圖6、 PSD-95和NMDA受體之次單元共軛免疫沈澱法………..31
第四章之圖目錄
圖1. 實驗設計架構之描敘………………………………………….41
圖2. 以A68930(2mg/kg)活化多巴胺D1/D5受體對缺氧實驗
動物之長期空間學習與記憶之效應………………………….46
圖3. 以A68930(2mg/kg)活化多巴胺D1/D5受體對缺氧實驗
動物CREBserine-133的磷酸化與PSD-95的表現程度之效應…47
圖4. 在有選擇性多巴胺D1/D5受體拮抗劑SCH23390的情況
下，活化多巴胺D1/D5受體對缺氧實驗動物CREBserine-133
的磷酸化與PSD-95的表現程度之效應………………………48
圖5. 活化多巴胺D1/D5受體對缺氧實驗動物NMDA受體次單元的效應…………………………………………………………….49
英文縮寫
aCSF artificial cerebrospinal fluid
ATF activating transcription factor
AMPA α-amino-3-hydroxy-5-methyl-4- isoxazoleproprionate
CaMK calmodulin kinase
cAMP 3'-5'-cyclic adenosine monophosphate
CRE cAMP response element
CREB cAMP response element binding protein
D1/D5R dopamine D1/D5 receptor
GABA γ-aminobutylic acid
ERK extracellular-signal regulated kinase
LTP long-term potentiation
MAPK mitogen-activated protein kinase
NMDA N-methyl-D-aspartate
PBS phosphate-buffered saline
PDZ PSD-95/discs large/zone occludens
PTZ pentylenetetrazol
nNOS neuronal nitric oxide synthase
pCREBSerine-133 Phosphorylated CREBSerine-133
PKA protein kinase A
PKC protein kinase C
PP-1 protein phosphatase-1
PP-2A protein phosphatase-2A
PSD postsynaptic density
PMSF phenylmethylsulphonylfluoride
PVDF poly-vinylidene difluoride filter
RSK ribosomal S6 kinase
SAP synapse-associated protein
SDS sodium dodecylsulfate
SynGap synatic RAS-GTPase activating protein








附錄目錄
附錄一、刊登於Epilepsia之論文
附錄二、刊登於Experimental Neurology之論文

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