利用果蠅探討思覺失調症相關基因 neurexin-1 對空間行為短期記憶之影響

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研究生：	于林生 Yu, Lin-Sheng
論文名稱：	利用果蠅探討思覺失調症相關基因 neurexin-1 對空間行為短期記憶之影響 Using Drosophila as a model organism to investigate the effect of schizophrenia-associated gene neurexin-1 in spatial behavior short-term memory.
指導教授：	張慧雲 Chang, Hui-Yun
口試委員:	汪宏達 Wang, Horng-Dar 羅中泉 Lo, Chung-Chuan
學位類別：	碩士 Master
系所名稱：	生命科學暨醫學院 - 系統神經科學研究所 Institute of Systems Neuroscience
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	41
中文關鍵詞：	思覺失調、果蠅、神經系統
外文關鍵詞：	Drosophila melanogaster, Schizophrenia, neuron
相關次數：	點閱：4 下載：0
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思覺失調症(schizophrenia)，早期又名精神分裂症，為一種導致社會行為異
常與認知混亂的精神疾病，臨床症狀包括幻覺、思維障礙、幻聽與社交功能障礙…
等，病患通常於青春期或成年期間罹患疾病。導致思覺失調症發生的主因目前包
含環境因素和基因因素，研究中顯示，長期的藥物濫用或是處於逆境成長的孩童，
均有很高的機率造成思覺失調症病發。而在基因因素方面，目前有許多研究證實
基因突變、單核甘酸多樣性(single nucleotide polymorphism; SNP)和複製數變異(copy number variation; CNV)均與思覺失調症的發生有相關，neurexin-1 則為其中候選基因之一。neurexin-1 為前突觸黏附蛋白，位於前突觸的表面，在前後突觸的連接中扮演重要的腳色，其作用與突觸囊泡(synaptic vesicle)的釋放和突觸的可塑性(synaptic plasticity)有相關，在部分患者中已發現此基因的突變或缺失。在此實驗中，利用果蠅作為模式生物來研究與人類同源的基因Drosophila neurexin 1 (dnrx)，在成蟲之後抑制其表達，對於大腦中神經元的型態、突觸功能以及空間短期記憶的影響。結果發現，當果蠅成蟲後，當抑制 neurexin 1 表現時，會造成果蠅大腦中神經元減少並影響突觸小泡的釋放，此現象可能與導致思覺失調症的原因有關，而在行為實驗中發現，果蠅的短期記憶產生缺陷。

Schizophrenia is a mental disorder which leads to abnormal behavior and cognitive disorder. The clinical symptoms include hallucinations, delusions, social withdrawal and disorganized thinking and speech etc. Schizophrenia most commonly happen between the ages of 16 and 30. The causes of schizophrenia include
environmental factors and genetic factors. The previous research observe that drug abuse or childhood trauma are high risks to result the people in schizophrenia. In genetic factors, such studys suggest that the mutation, single nucleotide polymorphism and copy number variation in some candidate genes may lead to
schizophrenia. One of those genes is neurexin-1 which encode the presynaptic adhesion protein neurexin-1. Neurexin-1 plays an important role in synaptic vesicle release and synaptic plasticity. Genetic deletion or mutation in neurexin-1 are found in some patients. In this study, we express the dnrx knockdown which is human homologous gene in adult Drosophila. The results show that dnrx knockdown may decrease the number of neurons in adult fly brain and the synaptic vesicular release were affected in this model. we also found that the short-term memory of Drosophila was deficit in the hehavior experiment.

摘要...................................................... I
Abstract.................................................. II Acknowledgement........................................... III Contents.................................................. IV Introduction.............................................. 1
1.Schizophrenia.......................................... 1
2. The environmental risk factors in schizophrenia....... 1
3. The genetic risk factors in schizophrenia............. 2
4. Human gene neurexin in schizophrenia.................. 3
5. The synapse in schizophrenia.......................... 4
6. Behavior of schizophrenia............................. 6
7. Model organism: Drosophila melanogaster............... 7
8. Drosophlia genes neurexin (dnrx)...................... 8 
Methods and materials..................................... 11
Drosophila stocks........................................ 11
Confocal images.......................................... 11
Behavior experiment...................................... 12
Statistical analysis..................................... 13 Results................................................... 14
The GFP signal is decreased in adult Drosophila head by dnrx
knockdown expressed after eclosion....................... 14
Dnrx knockdown result in reducing the synaptic vesicles release
in the drosophila brain.................................. 15
The short-term memory of Drosophila may impaired by dnrx
knockdown in behavior experiment......................... 16 Discussion................................................ 19
The morphological pattern of Drosophila neurons are affected by
expressing of neurexin after eclosion in pan-neuron...... 19
Synaptic exocytosis decreased by dnrx knockdown may cause by
calcium channel impaired in the synapses................. 20
The heterozygous dnrx mutation may affect behavior and short-
term memory in Drosophila................................ 21 Figures................................................... 23
Figure 1. The neurexin-neuroligin complex interacted in the
synaptogenesis. ......................................... 24
Figure 2. The protein structure of the human NRXNα, and
Drosophila NRX. ......................................... 25
Figure 3. The short-term spatial memory of Drosophila behavior
analysis and preform index............................... 26
Figure 4. The GAL4-UAS system was regulated by Tublin-GAL80ts at
different temperature.................................... 28
Figure 5. The Drosophila pan-neural expression pattern are
decreased by dnrx knockdown.............................. 30
Figure 6. Dnrx knockdown affected the synaptic vesicle release
function in Drosophila pan-neurons....................... 32
Figure 7. The short-term spatial memory of Drosophila seems no
different in high temperture enviroment.................. 33
Figure 8. The short-term spatial memory of Drosophila was
deficit in dnrx RNAi knockdown background................ 34
Figure 9. The Drosophila shrot-term spatial memory was disorder
by dnrx RNAi knockdown................................... 35 References................................................ 36 
                                

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