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研究生:裴如淳
研究生(外文):Ju-Chun Pei
論文名稱:以精神分裂症候選基因Nrg1缺損小鼠為模型-檢驗Nrg1調控海馬迴相關認知作業與海馬迴GABA中介神經元表現之效果
論文名稱(外文):Examination of the Sex-Specific Effect of Nrg1, a Candidate Gene for Schizophrenia, in the Regulation of Hippocampal Cognitive Functions and the Expression of Hippocampal GABAergic Interneurons – Using Neuregulin 1 Deficient Mice as a Model
指導教授:賴文崧賴文崧引用關係
口試委員:李立仁梁庚辰劉怡均劉智民
口試日期:2013-06-05
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:心理學研究所
學門:社會及行為科學學門
學類:心理學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:英文
論文頁數:163
中文關鍵詞:精神分裂症Nrg1行為表現型認知作業神經形態學GABA 中介神經元丙戊酸鈉
外文關鍵詞:schizophreniaNrg1behavioral phenotypingneuromorphologypentylenetetrazolGABAergic interneuronvalproate
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精神分裂症為一盛行率達 1%、造成認知缺損且遺傳性高之心理疾病。苦於致病機轉不明,在治療病人認知缺損症狀上始終效果不佳。故本研究主題為精神分裂症相關基因neuregulin 1(Nrg1)之致病機轉。多項研究指出Nrg1與海馬迴神經可塑性有關,其可能為導致精神分裂症病人認知缺損之病因。本研究利用Nrg1缺損小鼠,欲透過觀察認知行為表現,配合藥物操弄、神經型態研究、神經傳導物質表現量等多取向的實驗設計,來深入探討精神分裂症的認知缺損機轉。實驗一,欲分析基因對於不同性別之多項行為表現影響,著重於觀察此基因對於與學習記憶之影響。實驗發現Nrg1缺損會造成認知作業缺損,特別是在公鼠身上。而,兩個月和六個月大的Nrg1缺損小鼠在基礎行為測試表現正常,此可排除導致認知能力不佳之混淆變項。實驗二測試較易受到影響之神經傳導系統,觀察施打藥物後引發之行為反應。結果顯示Nrg1缺損公鼠之GABA神經傳導系統較脆弱。實驗三進一步觀察海馬迴之神經型態與GABA神經傳導物質表現量。Nrg1缺損小鼠雖無明顯地神經細胞型態改變,但在Nrg1缺損公鼠海馬迴的GABA中介神經元表現明顯低落。實驗四進一步使用 GABA相關抗癲癇藥-丙戊酸鈉(Valproate),成功扭轉其在認知作業上的缺損,以期提供病人藥物治療之發展方向。

Accumulating evidence from human and animal studies suggest that neuregulin 1 (Nrg1) might be involved in the neurodevelopment, GABAergic neurotransmission, and pathogenesis of schizophrenia. Nrg1 belongs to the neuregulin family of growth factors and its expression has been found in many brain regions, especially in the hippocampus. Emerging studies start to reveal that Nrg1 signaling is related to the neural plasticity which might be responsible for the cognitive deficits in schizophrenic patients. To determine the involvement of Nrg1 in cognitive functions and the importance of Nrg1 in the regulation of neuromorphology and neurochemicals in vivo, a new line of Nrg1 mice that carry a truncation of transmembrane (TMc) domain of Nrg1 from exon 9 were generated and used in this study. Both male and female TMc domain-Nrg1+/- mutant mice and their wild-type littermates were used in a series of 4 experiments. In Experiment 1, a comprehensive battery of cognitive-related tasks and basic behavioral tasks was applied to evaluate the behavioral phenotypes of our Nrg1+/- mutant mice. Nrg1+/- mice exhibited a normal profile of basic function but significant impairments in their cognitive functions, especially in males. Experiments 2 and 3 were conducted to reveal conceivable clues for interpreting the observed behavioral deficits. In Experiment 2, pharmacological challenges were conducted. Both males and females received an acute administration of MK-801, methamphetamine, and pentylenetetrazol, respectively. Our data indicated that the injection of PTZ induced significant behavioral alterations in male (but not female) Nrg1+/– mice whereas the other two drugs had no effect, suggesting a potential alteration of GABAergic activity in the brain of mutant males. Neuromorphological and neurochemical alterations in the hippocampus of mutant mice were further examined in Experiment 3, respectively. Neuromorphometric analysis of pyramidal neurons in the CA1 region of hippocampus in these mice revealed that no significant morphological alteration was found. However, a significant reduction of GAD67 and parvalbumin expression level was found in the hippocampus of Nrg1+/– mutant males but not in females. In Experiment 4, we found that the use of valproate, a GABA-related pharmacoepigenomic, successfully rescued observed cognitive deficits in male Nrg1+/– mutant mice. Collectively, these results indicate the importance of Nrg1 in the regulation of hippocampus-related cognitive functions and the expression of hippocampal GABAergic interneurons, especially in males.

致謝 i
摘要 iii
Abstract v
Table of Contents vii
Figures and Tables ix
Chapter 1 General Introduction 1
1. Overview of schizophrenia 1
2. The neurochemistry of schizophrenia 4
3. The etiology of schizophrenia 13
4. What is neuregulin 1 (NRG1)? 15
5. Using genetically engineered animal models to study the role of Nrg1 in the pathogenesis of schizophrenia 24
6. The objective of this study 33
References 39
Chapter 2 Sex- Specific Alteration of Cognitive Function and the Expression of GABAergic Interneurons in Hippocampus of Neuregulin 1 Deficient Mice 65
Introduction 65
Materials and Methods 70
Results 87
Discussion 91
References 120
Chapter 3 General Discussion 139
Nrg1 and the dysregulation of LTP 139
GABA hypothesis of schizophrenia as a primary etiology of schizophrenia 140
Nrg1 modulates sex-specific alteration on GABAergic transmission 142
The epigenetic processes of valproate in Nrg1 mutant 143
The foundation of “second hit”: Nrg1 deficit plays a critical role in interacting with environmental insults 144
All roads lead to common pathway? Different genetic alteration leads to diversity of clinical symptoms of schizophrenia 147
Rethinking biological psychiatry: Nrg1 polymorphisms may confer a wider susceptibility of psychiatric illness 148
References 150
Appendix 159


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