精神分裂症，又稱思覺失調症(Schizophrenia)，為一種精神疾病，患者的臨床症狀有幻聽、幻視、異常的社會行為和認知障礙，發病年齡通常為青春期到成年期間。造成思覺失調症的原因包含環境因素和遺傳因素，在過去研究顯示，藥物的濫用、營養失衡和生活環境的巨變均有很高的機率導致思覺失調症。在遺傳因素中，目前已經有多個研究證實許多基因突變或是單核苷酸多態性(single nucleotide polymorphism; SNP)、複製數變異(copy number variation; CNV)的異常均為導致思覺失調症的原因之一。而其中候選基因neruexin-1為連接前後突觸的重要蛋白質之一，對於突觸囊泡(synaptic vesicle)的釋放和突觸的可塑性(synaptic plasticity)扮演重要的角色，此基因的缺失和突變在思覺失調症的患者中已被發現。在此研究中，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)在成蟲大腦中神經元的型態與突觸的功能。結果發現抑制dnrx的表達後，在果蠅大腦的觸角葉(antennal lobe)有神經元、軸突與樹突都有減少的現象。而在果蠅的嗅覺系統中，抑制dnrx的表達會造成嗅覺受體神經元(olfactory receptor neurons)的突觸缺失，影響突觸小泡的釋放與突觸的可塑性。而此現象可能與導致思覺失調症的原因有關，對日後在生物腦中研究思覺失調症的致病機轉中有所貢獻。

Schizophrenia is a mental disorder. The clinical symptoms of this disorder are auditory hallucinations, abnormal social behavior and cognitive impairment. The age of onset is usually from adolescence to adulthood. Causes of schizophrenia include environmental factors and genetic factors. Previous studies show that drug abuse, nutritional imbalance and changes in the living or working environment are high risks to cause the people with schizophrenia. In genetic factors, many studies have confirmed that the mutation, single nucleotide polymorphism and copy number variation in some genes may lead to schizophrenia. One of the candidate genes in human is neruexin-1which plays an important role in synaptic vesicle release and synaptic plasticity. Genetic deletion and mutation in this gene are found in some patients. In this study, we used Drosophila as a model organism to investigate the molecular pathogenesis our result showed that dnrx pan-neuronal knockdown may cause the loss of axons and dendrites in the adult brains. In the fly olfactory system, the synaptic function and synaptic vesicular release were affected in this model. The pre- and post- synaptic dysfunction was identified that have established a dnrx animal model to further testing the connectomic pathogenesis of schizophrenia.

摘要 I
Abstract II
Acknowledgement III
Contents IV
Introduction 1
1. Schizophrenia 1
2. Environmental and genetic risk factors in schizophrenia 1
3. The synapse in schizophrenia 2
4. Human gene neurexin in schizophrenia 4
5. Mouse gene neurexin in schizophrenia 6
6. Model organism: Drosophila melanogaster 6
7. Drosophila gene neurexin (dnrx) 7
Materials and Methods 9
1. Drosophila stocks 9
2. Confocal images 9
3. Statistical analysis 10
Results 11
dnrx knockdown decreased the GFP signal in the adult Drosophila brain. 11
dnrx knockdown affected the neuronal function in the Drosophila olfactory system. 13
dnrx knockdown reduced the synaptic vesicles release in the Drosophila olfactory system. 14
dnrx knockdown affected the synapses connectivity in the Drosophila olfactory system. 16
Discussion 18
The expression pattern of Drosophila neurexin in pan-neuron 18
dnrx knockdown decreased the synaptic exocytosis in the synapses may cause by calcium channel impaired. 19
dnrx knockdown led to the synaptic dysfunction in the olfactory system in Drosophila may affect the sleep, learning, and memory. 20
The heterozygous dnrx mutation may affect other protein function and lead to the synaptic dysfunction. 21
Figures 25
Figure 1. The neurexin-neuroligin complex interacted in the synaptogenesis. 25
Figure 2. The protein structure of the human NRXNα, mouse nrxn and Drosophila dnrx. 27
Figure 3. dnrx Knockdown reduced the expressions pattern in Drosophila pan-neuron. 30
Figure 4. dnrx knockdown affected the axon function in Drosophila brain. 32
Figure 5. dnrx knockdown reduced the dendrites in Drosophila brain. 34
Figure 6. dnrx knockdown led to the synaptic vesicle exocytosis dysfunction in Drosophila brain. 36
Figure 7. dnrx Knockdown decreased the GFP signal in Drosophila olfactory system. 38
Figure 8. dnrx knockdown affected the synaptic vesicle release function in Drosophila olfactory system. 41
Figure 9. dnrx knockdown affected the synaptic connectivity in Drosophila olfactory system. 44
References 46

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