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標題: | 前腦興奮性神經元中缺損Disc1基因之小鼠的表現型鑑定 Phenotypic characterization of mice lacking exons 4-13 of Disc1 gene in forebrain excitatory neurons |
作者: | Pei-Fen Siow 蕭佩芬 |
指導教授: | 李立仁(Li-Jen Lee) |
關鍵字: | Disrupted-in-Schizophrenia 1 (DISC1),思覺失調症,應激表現,內側前額葉皮質,第二、三層錐狀神經元,抑制性神經元, Disrupted-in-Schizophrenia 1 (DISC1),schizophrenia,stress coping behavior,medial prefrontal cortex (mPFC),layer II/III pyramidal neurons,inhibitory interneurons, |
出版年 : | 2019 |
學位: | 碩士 |
摘要: | 思覺失調症是一種多致病因子的慢性精神疾病,患者的病徵是具有幻聽幻覺、行為異常、無法辨別幻覺與現實等。先前研究發現,許多基因與思覺失調症的發病機理有關,而其中一種基因是Disrupted-in-Schizophrenia 1(DISC1)。先前有研究發現在一群具有神經認知障礙的台灣思覺失調症患者身上,有一類極短型的DISC1被過度表達,而這樣的情形可能與患者的持續性專注力受損有關。在本篇研究中,為了研究極短型的DISC1對大腦的結構和功能有什麼影響,我們使用Cre / loxP系統使得小鼠前腦興奮性神經元中Disc1基因4至13的外顯子在Cre的作用下被剔除。我們利用前腦興奮性神經元中Disc1被剔除的基因突變鼠(FbDisc1 KO mice),進行了一系列的行為鑑定與大腦組織的分析。研究中,我們使用了8-12週齡大的公鼠做實驗,以純合子(Homo,Disc1Δ4-13/ Δ4-13; Emx1-Cre)和異型合子(Het,Disc1Δ4-13/ +; Emx1-Cre)的FbDisc1 KO 小鼠與年齡、性別匹配的對照組(Ctrl,Emx1-Cre)作比較。
首先,我們發現Homo和Het的FbDisc1 KO小鼠的外表與Ctrl組相比並沒有明顯的異常。此外,FbDisc1 KO小鼠在開放場地(open field test)、高架型迷宮(elevated plus maze test)、Y字型迷宮(Y maze test)、辨別新物體(novel object recognition test)和前脈衝抑制(prepulse inhibition test)的測試中皆表現正常。然而,Homo小鼠在強迫游泳試驗中表現出異常的應激反應。囓齒動物的內側前額葉皮層(mPFC)參與應激應對行為,於是我們進一步檢查了mPFC中神經元的組織學特徵。我們發現FbDisc1 KO小鼠大腦mPFC的第二、三層中的錐狀神經元,其樹突(dendrite)複雜程度並沒有改變,但是樹突棘(dendritic spine)的密度在Homo小鼠中卻顯著降低。另外,思覺失調症患者的前額葉皮質被證實存在抑制性神經元的缺損,因此我們利用組織免疫染色法來觀察FbDisc1 KO小鼠的抑制性神經元。我們發現Het和Homo小鼠的mPFC中,parvalbumin抑制性神經元的密度與Ctrl組相比並無差異;然而與Ctrl組相比,calbindin抑制性神經元的密度在Het和Homo組均顯著下降。 在維持專注力時,需要皮質與紋狀體互相投射的神經網絡所調控,而前額葉皮質在維持專注力扮演重要的角色。根據行為與組織分析的結果,我們認為極短型DISC 1藉由影響前額葉的功能,導致病人出現持續性專注力受損的問題。因此,我們的Homo小鼠是一種可以模擬具有極短型DISC1的思覺失調症患者的認知功能受損的動物模式。 Schizophrenia is a chronic psychotic disorder characterized by abnormal behavior and unable to interpret the reality. One susceptibility gene related to the pathogenesis of this disorder is Disrupted-in-Schizophrenia 1 (DISC1). Overexpressed extra-short DISC1 isoform was found in a neurocognitive subgroup of schizophrenia patients from Taiwan and might be related to their deficits in sustained attention. In the present study, in order to investigate the effects of extra-short DISC1 isoform on brain structure and function, we generated forebrain-specific Disc1 knockout (FbDisc1 KO) mice in which exons 4 to 13 of Disc1 gene was removed in forebrain excitatory neurons using the Cre/loxP system. The phenotypes of male adult (8-12 weeks old) homozygote (Homo, Disc1Δ4-13/Δ4-13; Emx1-Cre) and heterozygote (Het, Disc1Δ4-13/+; Emx1-Cre) FbDisc1 KO mice were compared with age- and sex-matched controls (Emx1-Cre). Homo and Het FbDisc1 KO mice were apparently normal with no significant physical impairment and behaved normally in the open field, elevated plus maze, Y-maze, novel object recognition and pre-pulse inhibition tests. However, Homo FbDisc1 KO mice exhibited altered stress-coping response in the forced swimming test. The medial prefrontal cortex (mPFC) in rodents is involved in the stress-coping behavior, we then examined the histological features of mPFC neurons. The dendritic complexity of layer II/III pyramidal mPFC was not altered in mutants while the dendritic spines were reduced in both Homo and Het FbDisc1 KO mice. The densities of parvalbumin-positive mPFC neurons were similar among control, Het and Homo mice; however, the densities of calbindin-positive mPFC neurons were reduced in both Homo and Het FbDisc1 KO mice. Together with the prefrontal cortex, intact cortical-striatal neural network is required for sustained attention. Based on the findings in the mPFC of Homo FbDisc1 KO mice, we suggest that our Homo FbDisc1 KO mice might model the neurocognitive phenotype of schizophrenia patients with extra-short DISC1 isoform. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73031 |
DOI: | 10.6342/NTU201901407 |
全文授權: | 有償授權 |
顯示於系所單位: | 解剖學暨細胞生物學科所 |
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