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題名 瑞特氏症模式小鼠的運動障礙與紋狀體特性之表型分析
Phenotypical analysis of motor behaviors and striatal characteristics in mouse models of Rett Syndrome
作者 蘇三華
Su, San Hua
貢獻者 廖文霖
蘇三華
Su, San Hua
關鍵詞 紋狀體
第二型甲基CpG結合蛋白
瑞特氏症
自閉症
運動障礙
striatum
MeCP2
Rett syndrome
autism
motor dysfunction
日期 2010
上傳時間 12-Apr-2012 14:12:30 (UTC+8)
摘要 瑞特氏症(Rett syndrome, RTT)為第二型甲基化CPG結合蛋白(2methyl-CpG binding protein 2, MeCP2)基因發生突變所造成的神經發育疾病，其症狀包含了嚴重的運動障礙及自閉傾向等特徵。由於紋狀體(striatum)為運動控制的重要腦區，我們假設RTT的運動障礙主要為紋狀體的功能異常所造成，故利用RTT模式小鼠來研究紋狀體是否為RTT運動障礙的致病原因。利用敞箱試驗(open field test)及加速滾輪測試(accelerating rotarod task)結果發現，Mecp2基因剔除小鼠的活動力明顯下降，並伴隨有運動協調能力的缺失。以免疫組織染色法及西方點墨法分別標定紋狀體中的mu-opioid receptor及calbindin蛋白，發現二者表現量均有明顯下降，然而表現parvalbumin的中間神經元細胞數目卻大量增加。我們發現在紋狀體中多巴胺D2受體的表現量顯著增加，但多巴胺合成酶tyrosine hydroxylase與多巴胺訊號傳遞下游分子DARPP-32蛋白並沒有明顯減少。為了更進一步確認紋狀體的致病角色，我們利用特定在紋狀體中缺少MeCP2的「Mecp2條件缺失小鼠」，觀察其運動行為的改變。結果發現，Mecp2條件缺失小鼠不管是在活動力或是運動學習上都表現出和Mecp2基因剔除小鼠相似的運動障礙，顯示紋狀體所調控的正常活動力及運動學習能力皆需要MeCP2的參與。我們接著進一步探討是否擁有完整MeCP2表現的紋狀體就足以執行正常的運動功能。當Mecp2基因剔除小鼠的紋狀體重新表現MeCP2(即「Mecp2條件回復小鼠」)，MeCP2缺失所造成的運動障礙可被回復到接近野生型小鼠運動能力的正常水準。顯示紋狀體中MeCP2的存在為正常運動控制的充要條件。在以cyclin-dependent kinase-like 5 (Cdkl5)突變小鼠研究MeCP2的磷酸化是否會影響到運動行為，發現Cdkl5突變小鼠在出生早期及成年時期皆存在與Mecp2基因剔除小鼠一致的運動協調能力缺失。免疫組織染色及西方點墨法結果顯示，Cdkl5突變小鼠的紋狀體中mu-opioid receptor表現量有明顯下降，但parvalbumin的中間神經元數目並無改變，而在大腦皮質中多巴胺轉運子DAT1蛋白表現量明顯上升。CDKL5突變造成與RTT相似症狀的原因還須更進一步的探討。綜上所述，本研究為「紋狀體異常可能為RTT運動障礙的主要致病原因」提供動物模式的實驗證據，並提供了一個新的觀點用於未來治療RTT或防止其症狀的惡化。
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描述 碩士
國立政治大學
神經科學研究所
98754001
99
資料來源 http://thesis.lib.nccu.edu.tw/record/#G0098754001
資料類型 thesis
dc.contributor.advisor 廖文霖zh_TW
dc.contributor.author (Authors) 蘇三華zh_TW
dc.contributor.author (Authors) Su, San Huaen_US
dc.creator (作者) 蘇三華zh_TW
dc.creator (作者) Su, San Huaen_US
dc.date (日期) 2010en_US
dc.date.accessioned 12-Apr-2012 14:12:30 (UTC+8)-
dc.date.available 12-Apr-2012 14:12:30 (UTC+8)-
dc.date.issued (上傳時間) 12-Apr-2012 14:12:30 (UTC+8)-
dc.identifier (Other Identifiers) G0098754001en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/52637-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 神經科學研究所zh_TW
dc.description (描述) 98754001zh_TW
dc.description (描述) 99zh_TW
dc.description.abstract (摘要) 瑞特氏症(Rett syndrome, RTT)為第二型甲基化CPG結合蛋白(2methyl-CpG binding protein 2, MeCP2)基因發生突變所造成的神經發育疾病，其症狀包含了嚴重的運動障礙及自閉傾向等特徵。由於紋狀體(striatum)為運動控制的重要腦區，我們假設RTT的運動障礙主要為紋狀體的功能異常所造成，故利用RTT模式小鼠來研究紋狀體是否為RTT運動障礙的致病原因。利用敞箱試驗(open field test)及加速滾輪測試(accelerating rotarod task)結果發現，Mecp2基因剔除小鼠的活動力明顯下降，並伴隨有運動協調能力的缺失。以免疫組織染色法及西方點墨法分別標定紋狀體中的mu-opioid receptor及calbindin蛋白，發現二者表現量均有明顯下降，然而表現parvalbumin的中間神經元細胞數目卻大量增加。我們發現在紋狀體中多巴胺D2受體的表現量顯著增加，但多巴胺合成酶tyrosine hydroxylase與多巴胺訊號傳遞下游分子DARPP-32蛋白並沒有明顯減少。為了更進一步確認紋狀體的致病角色，我們利用特定在紋狀體中缺少MeCP2的「Mecp2條件缺失小鼠」，觀察其運動行為的改變。結果發現，Mecp2條件缺失小鼠不管是在活動力或是運動學習上都表現出和Mecp2基因剔除小鼠相似的運動障礙，顯示紋狀體所調控的正常活動力及運動學習能力皆需要MeCP2的參與。我們接著進一步探討是否擁有完整MeCP2表現的紋狀體就足以執行正常的運動功能。當Mecp2基因剔除小鼠的紋狀體重新表現MeCP2(即「Mecp2條件回復小鼠」)，MeCP2缺失所造成的運動障礙可被回復到接近野生型小鼠運動能力的正常水準。顯示紋狀體中MeCP2的存在為正常運動控制的充要條件。在以cyclin-dependent kinase-like 5 (Cdkl5)突變小鼠研究MeCP2的磷酸化是否會影響到運動行為，發現Cdkl5突變小鼠在出生早期及成年時期皆存在與Mecp2基因剔除小鼠一致的運動協調能力缺失。免疫組織染色及西方點墨法結果顯示，Cdkl5突變小鼠的紋狀體中mu-opioid receptor表現量有明顯下降，但parvalbumin的中間神經元數目並無改變，而在大腦皮質中多巴胺轉運子DAT1蛋白表現量明顯上升。CDKL5突變造成與RTT相似症狀的原因還須更進一步的探討。綜上所述，本研究為「紋狀體異常可能為RTT運動障礙的主要致病原因」提供動物模式的實驗證據，並提供了一個新的觀點用於未來治療RTT或防止其症狀的惡化。zh_TW
dc.description.tableofcontents 誌謝 ..................................................................................................................I
     中文摘要 ..........................................................................................................II
     英文摘要 .........................................................................................................III
     目錄 ................................................................................................................IV
     圖次 ..............................................................................................................VIII
     縮寫對照表 ................................................................................................................IX
     第一章 緒論.................................................................................................. 01
     第一節 泛自閉症障礙 (Autism spectrum disorder, ASD)........................... 01
     一、ASD的病患存在運動障礙.................................................................. 01
     二、ASD具高度遺傳異質性...................................................................... 02
     第二節 瑞特氏症 (Rett Symdrome, RTT) .................................................. 02
     一、RTT的起源........................................................................................ 02
     二、RTT的症狀特徵................................................................................. 03
     三、RTT及自閉症 (Autism)之間的關聯.................................................... 03
     四、RTT的病源學..................................................................................... 04
     五、MeCP2蛋白....................................................................................... 04
     六、MECP2基因參與神經發育................................................................. 05
      七、瑞特氏症模式小鼠 (Mouse models of RTT) ...................................... 06
     八、非典型瑞特氏症 (Atypical Rett Syndrome) ....................................... 07
      第三節 運動控制的神經迴路....................................................................... 08
     一、基底核 (basal ganglia) ...................................................................... 08
      (一)直接路徑 (Direct pathway) ........................................................... 08
      (二)間接路徑 (Indirect pathway) …................................................... 09
      二、紋狀體 (striatum) .............................................................................. 09
      (一)紋狀體的細胞組成.......................................................................... 09
      (二)紋狀體的區間分隔 (compartmentalization)….............................. 11
      (三)紋狀體與疾病的關聯...................................................................... 11
     第四節 實驗目的與策略.............................................................................. 12
     第二章 材料與方法.................................................................................................. 14
      第一節 實驗動物......................................................................................... 14
      第二節 基因轉殖小鼠之基因型鑑定 (Genotypiing).................................... 14
     一、Genomic DNA之萃取........................................................................ 14
     二、Mecp2基因剔除小鼠之基因型鑑定.................................................... 14
     三、Cdkl5突變鼠之基因型鑑定................................................................. 15
     四、Dlx5/6-Cre基因轉殖鼠之基因型鑑定................................................. 15
     五、Flox-Mecp2基因轉殖鼠之基因型鑑定................................................ 16
     六、Flox-STOP基因轉殖鼠之基因型鑑定................................................. 16
      第三節 成年小鼠的行為測試.....……………................................................ 16
     一、敞箱試驗 (Open Field Test) .............................................................. 16
     二、加速滾輪測試 (Accelerating Rotarod Test)........................................ 17
     第四節 出生後幼鼠之行為測試 (perinatal behavior) ................................. 17
     一、平面翻正測試 (Surface Righting Test, SR)........................................ 17
      二、背地性翻轉測試 (Negative Geotaxis Test, NG)………….............................. 17
      三、抓繩試驗 (Wire Suspension Test, WS)……………….................................... 18
     第五節 免疫組織染色法 (Immunohistochemistry)............................................... 18
      一、腦組織的灌流製備與切片 .............................................................................. 18
     二、腦組織染色 ................................................................................................... 18
      三、免疫染色之定量分析...................................................................................... 19
      (一) MOR表現量分析.........................................................................................19
      (二)Calbindin+細胞計數………………..............................................................19
     (三) Parvalbumin+細胞計數……………........................................................... 20
     (四)TH及D32表現量分析…………….…......................................................... 20
     第六節 西方點墨法 (Western blot) ..................................................................... 20
     一、腦組織取樣.................................................................................................... 20
      二、腦組織蛋白質萃取......................................................................................... 20
     三、蛋白質濃度測定............................................................................................. 21
     四、西方點墨法.................................................................................................... 21
     五、西方點墨法之定量分析.................................................................................. 22
     第三章 結果 (Results)…………................................................................................ 23
     第一節 Mecp2基因剔除小鼠存在運動障礙............................................................ 23
     第二節Mecp2基因剔除小鼠之紋狀體中分子表現與細胞組成的改變...................... 27
     (一)Mecp2 基因剔除小鼠的紋狀體中mu opioid receptor表現量下降................. 27
     (二)Mecp2 基因剔除小鼠的紋狀體中Calbindin+神經細胞密度增加但表現
     量下降................................................................................................................. 29
     (三)Mecp2基因剔除小鼠表現parvalbumin的神經細胞數增加............................ 31
      (四)Mecp2基因剔除小鼠tyrosine hydroxylase (TH)表現量無明顯改變...............33
      (五)Mecp2基因剔除小鼠的紋狀體中D2R表現量明顯增加................................. 35
     (六)Mecp2基因剔除小鼠的紋狀體中DARPP-32 (D32)無明顯改變..................... 36
     第三節 Mecp2條件缺失小鼠... .............................................................................. 38
     第四節 Mecp2條件回復小鼠.................................................................................. 42
     第五節 Cdkl5突變小鼠的運動能力........................................................................ 47
     第六節 Cdkl5突變小鼠在出生後的運動能力.......................................................... 51
     第七節 Cdkl5突變小鼠之紋狀體中分子表現與細胞組成的改變............................. 54
     (一)Cdkl5突變小鼠的紋狀體中mu opioid receptor表現量明顯下降.................... 54
     (二)Cdkl5突變小鼠表現parvalbumin的神經細胞數目無明顯改變...................... 56
     (三)Cdkl5突變小鼠dopamine transporter (DAT1) 表現量在大腦皮質明顯上升.. 58
     (四)Cdkl5突變小鼠在MeCP2蛋白上絲胺酸421的磷酸化並無明顯改變.............59
     第四章 討論............................................................................................................... 60
     一、 RTT為一個好的模式來研究ASD存在的運動缺失........................................... 60
     二、Mecp2基因剔除小鼠存在活動力下降且運動協調能力缺失的現象.................... 61
     三、MeCP2的缺失造成紋狀體的分子表現異常及結構改變..................................... 61
     (一)MeCP2的缺失造成紋狀體的MOR表現減少................................................. 61
     (二) MeCP2的缺失造成紋狀體Calbindin+細胞數增加，但Calbindin蛋白質表現減少........................................................................................................................ 63
     (三)MeCP2的缺失造成紋狀體的Parvalbumin+細胞數增加................................ 64
     (四) MeCP2的缺失改變紋狀體的多巴胺神經傳遞系統的分子表現..................... 65
     四、紋狀體中MeCP2存在與否影響到運動的功能....................................................66
     五、Cdkl5突變小鼠的運動功能障礙........................................................................ 68
     六、Cdkl5的缺失造成紋狀體的分子表現異常.......................................................... 70
     第五章 結論................................................................................................................72
     參考文獻. .................................................................................................................. 73
     附錄一..........................................................................................................................X
     附錄二.........................................................................................................................XI		zh_TW
dc.language.iso en_US-
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0098754001en_US
dc.subject (關鍵詞) 紋狀體zh_TW
dc.subject (關鍵詞) 第二型甲基CpG結合蛋白zh_TW
dc.subject (關鍵詞) 瑞特氏症zh_TW
dc.subject (關鍵詞) 自閉症zh_TW
dc.subject (關鍵詞) 運動障礙zh_TW
dc.subject (關鍵詞) striatumen_US
dc.subject (關鍵詞) MeCP2en_US
dc.subject (關鍵詞) Rett syndromeen_US
dc.subject (關鍵詞) autismen_US
dc.subject (關鍵詞) motor dysfunctionen_US
dc.title (題名) 瑞特氏症模式小鼠的運動障礙與紋狀體特性之表型分析zh_TW
dc.title (題名) Phenotypical analysis of motor behaviors and striatal characteristics in mouse models of Rett Syndromeen_US
dc.type (資料類型) thesisen
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