臺灣博碩士論文加值系統

神經突觸的發育以及功能往往會受到環境的影響。此外，神經膠細胞在調控神經突觸的形態及功能扮演很重要的角色。然而，神經膠細胞如何偵測環境的改變，進而影響神經突觸的發育及功能，仍是需要探討的問題。在此論文中，我們觀察到兩株基因突變果蠅：trachealess/NPAS1/3 和 dysfusion/NPAS4的神經肌肉結合處 (neuromuscular junctions) 之神經突觸，無論在形態上或功能上，都有很明顯的變化。在trachealess (trh) 的基因突變果蠅中，我們觀察到神經突觸小結 (synaptic boutons) 的型態有異常的變化：型態較小的突觸小結聚集在正常型態的突觸小結附近，此異常聚集的小型突觸小結稱為衛星小結 (satellite boutons)。我們進一步地分析導致此衛星小結之異常型態的原因。在trh基因突變果蠅中，果蠅的氣管系統，亦即呼吸系統，有很嚴重的結構缺陷，部分斷裂的氣管導致果蠅處於低氧的狀態，此低氧狀態進而影響果蠅的神經膠細胞型態，包覆更多的神經突觸小結。缺氧誘導因子 (hypoxia-inducible factor (HIF)-1/Similar (Sima)) 的過度表現促使 Wnt/Wingless (Wg) 訊號在神經膠細胞內增加，導致衛星小結的形成。然而，衛星小結的增加仍維持著神經突觸小結的正常功能，例如：神經傳導物質的傳送。而神經傳導物質的傳送，對於果蠅幼蟲的爬行是很重要的關鍵。另外，我們發現dysfusion (dys) 表現在神經膠細胞中，亦會調控神經突觸的發育，在dys基因突變果蠅中，同樣會造成衛星小結的增加。

Synaptic structure and activity are sensitive to environmental alterations. Modulation of synaptic morphology and function is often induced by signals from glia. However, the process by which glia mediate synaptic responses to environmental perturbations such as hypoxia remains unknown. Here, I used Drosophila neuromuscular junctions (NMJs), which are enwrapped and remodeled by the glia, as a model to address this question.
First part of my study shows that in the mutant for Trachealess (Trh), the Drosophila homolog for NPAS1 and NPAS3, smaller synaptic boutons form clusters named satellite boutons appear at larval NMJs, which is induced by the reduction of internal oxygen levels due to defective tracheal branches. Thus, the satellite bouton phenotype in the trh mutant is suppressed by hyperoxia, and recapitulated in wild-type larvae raised under hypoxia. I further show that hypoxia-inducible factor (HIF)-1/Similar (Sima) is critical in mediating hypoxia-induced satellite bouton formation. Sima upregulates the level of the Wnt/Wingless (Wg) signal in glia, leading to reorganized microtubule structures within presynaptic sites. Finally, hypoxia-induced satellite boutons maintain normal synaptic transmission at the NMJs, which is crucial for coordinated larval locomotion. Interestingly, the trh mutant shows uncoordinated crawling, which might result from the differential morphological and physiological changes of anterior and posterior segments. Nevertheless, the critical evidence for the correlation between differential morphology and the uncoordinated crawling is limited and needed further study.
Second, I show that satellite bouton appeared in the mutant for Dysfusion (Dys), the Drosophila homolog for NPAS4. Interestingly, Dys might be expressed in glia to influence synapse formation.

Acknowledgments..................................................................................................i
中文摘要.........................................................................................................ii
Abstract.........................................................................................................iii
Chapter 1 Introduction...........................................................................................1
1.1 Tripartite synapse coupling with tracheal system.............................................................1
1.2 The development of tracheal system...........................................................................3
1.3 Using Drosophila larval neuromuscular junctions as a model to study synapse development......................5
1.4 The role of glia in the synapse formation....................................................................10
1.5 Hypoxia responses in various systems.........................................................................12
1.6 The role of NPAS1/3 and NPAS4 in the mammals and Drosophila melanogaster.....................................15
1.7 Crawling behavior............................................................................................17
Chapter 2 Materials and Methods..................................................................................19
2.1 Fly stocks...................................................................................................19
2.2 Hypoxia or hyperoxia rearing condition.......................................................................19
2.3 Immunostaining...............................................................................................20
2.4 Heat fixation................................................................................................21
2.5 Image processing and Data analysis...........................................................................22
2.6 RT-PCR.......................................................................................................23
2.7 Western blot.................................................................................................24
2.8 Electrophysiological recordings..............................................................................25
2.9 Crawling behavior............................................................................................25
2.10 Statistics..................................................................................................26
Chapter 3 Results................................................................................................27
3.1 trh modulates synaptic bouton formation non-cell autonomously................................................27
3.2 Hypoxia induces satellite bouton formation...................................................................29
3.3 Glial HIF-1/Sima mediates satellite bouton formation.......................................................30
3.4 Wg signals mediate glial Sima activity to modulate bouton morphology.........................................32
3.5 Presynaptic Wg signaling modulates bouton morphology in the trh mutant.......................................34
3.6 Impaired crawling behavior in the trh mutant.................................................................35
3.7 Dys regulates synaptic bouton morphology in glia.............................................................37
Chapter 4 Discussion.............................................................................................39
4.1 Hypoxia caused by the defective tracheal system induces abnormal synapses in the trh mutant..................39
4.2 Glia play a critical role in satellite bouton formation in response to hypoxia...............................40
4.3 Glial invasions onto synaptic boutons associate with synapse growth..........................................41
4.4 Sima elevates Wg signal expression in glia to modulate the satellite bouton formation........................43
4.5 Hypoxia disturbs synaptic function...........................................................................44
4.6 Satellite bouton phenotype in the trh mutant.................................................................45
4.7 Differential morphological and physiological changes of anterior and posterior segments in the trh NMJs......46
4.8 Glial Dys modulates the NMJ development......................................................................48
List of Figures
Figure 1. Satellite bouton formation at trh NMJs.................................................................50
Figure 2. Presynaptic and postsynaptic structures at trh NMJs....................................................52
Figure 3. Satellite bouton formation is non-cell autonomously regulated by trh in trachea........................54
Figure 4. Tracheal defects in the trh mutant.....................................................................56
Figure 5. Hypoxia biosensor GFP-ODD responds in trh mutant.......................................................57
Figure 6. Induction of satellite boutons in trh mutant by hypoxia................................................58
Figure 7. Glial Sima induces satellite bouton formation..........................................................59
Figure 8. Satellite bouton induction by glial Sima in the trh mutant.............................................60
Figure 9. Sima upregulation in hypoxia and the trh mutant........................................................62
Figure 10. Glial Wg induction through Sima at trh NMJs...........................................................64
Figure 11. Neuronal and glial Wg modulates synapse growth at trh NMJs............................................66
Figure 12. Presynaptic Wg signaling modulates synapse growth at trh NMJs.........................................68
Figure 13. Glial processes at synaptic regions at trh NMJs.......................................................70
Figure 14. Impaired crawling behavior of the trh mutant..........................................................71
Figure 15. Selective satellite bouton formation at anterior segments of trh NMJs.................................73
Figure 16. Wg and Sima have minor effects on satellite bouton formation in A6 segment of the trh mutant..........74
Figure 17. Synaptic transmission at trh NMJs.....................................................................76
Figure 18. Satellite bouton formation at dys NMJs................................................................78
Figure 19. Schematic model for satellite bouton induction and crawling defects in the trh mutant.................80
List of Table
Table. Detail statistical data in all figures....................................................................82
References.......................................................................................................88

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