臺灣博碩士論文加值系統

神經系統發育異常被認為會導致特定精神疾病之形成，包括自閉症，精神分裂以及注意力不足過動症。特定之環境因子與基因缺陷已被證實與神經系統發育異常密切相關。最為人知的環境因子為妊娠早期感染所導致之免疫系統活化而引起之大量細胞激素表現。暴露在異常的細胞激素環境被認為是影響胎兒神經發育病導致精神疾病之主因，但詳細機制未明。在此研究，我著重於Sarm1蛋白在神經細胞免疫反應中所扮演的角色及其與神經發育缺陷所導致疾病之相關性。早期在先天性免疫系統的研究，發現Sarm1可透過競爭TRIF蛋白而調控類鐸受體三、四之訊息傳導，因此被認為是先天免疫系統中的負調控因子。本實驗室的近期研究發現，Sarm1在大腦中的表現量極高並且透過影響細胞骨架中微管的穩定性而調控神經元型態發育過程。Sarm1具有同時調控類鐸受體之訊息傳遞及神經元形態發育過程的分子特性，讓我們認為Sarm1可能是串聯先天免疫反應以及神經發育的重要關鍵。因此我建立了利用微型核糖核酸降低Sarm1表現量的基因轉殖小鼠模型以利於在活體動物中研究Sarm1在大腦的功能。研究結果顯示，缺少Sarm1表現會造成胎鼠大腦及成鼠皮質中細胞激素的表現失衡。同時，降低Sarm1表現會使小鼠大腦變小並導致類似自閉症之行為，包括的缺乏認知彈性，學習障礙以及減少社會行為。除了影響神經細胞型態發育，Sarm1亦涉及突觸可塑性之調控。在海馬迴CA1區域，缺少Sarm1表現的小鼠其由代謝性麩胺酸受體所媒介的長期抑制效應嚴重缺損，然而由NMDA受體所媒介的突觸可塑性則有增強現象。進一步分析突觸之蛋白質表現後發現突觸後的組成分子在Sarm1缺少小鼠中的表現量與野生型小鼠不同。這些結果顯示Sarm1對於維持突觸組成及功能的重要性。對Sarm1缺少小鼠的施予正向異位性調節分子(CDPPB)，來提高代謝性麩胺酸受體功能後，突觸活性以及類自閉症行為即可以獲得改善。此結果指出Sarm1藉由調控代謝性麩胺酸受體的活性而影響小鼠行為表現並且呼應目前代謝性麩胺酸受體被認為在自閉症所扮演的重要角色。總結本篇論文的研究證實了Sarm1可以作用於調控神經元的先天免疫系統和形態發生並影響突觸可塑性。透過這些調控機制，進而在Sarm1缺少的情況下導致小鼠類似自閉症行為。 

Neurodevelopmental disorders, including autism, schizophrenia and attention deficiency and hyperactivity disorder, are complex neuropsychiatric diseases. Both environmental factors and genetic deficits contribute to the pathogenesis of neurodevelopmental disorders. The most well-known environmental factor is prenatal immune challenge caused by infection. Robust cytokine production induced by inflammatory response is believe to affect neural development and leads to several psychiatric disorders. However, the detail mechanism is not clear yet. In this study, I focus on the role of Sarm1 in neuronal immunity and its involvement in neurodevelopmental disorder. Sarm1is originally identified as a negative regulator of TRIF-dependent TLR3/TLR4 pathways in peripheral innate immune system. We recently showed that Sarm1 is highly expressed in brain and plays critical roles in regulating neural morphogenesis by regulating microtubule stability. The dual roles of sarm1 in both TLR3/4 signaling and neuronal morphogenesis suggest a possibility for Sarm1 to mediate crosstalk between innate immunity and neurodevelopment. Therefore, I established Sarm1 knockdown transgenic mice model to study its function in vivo. In Sarm1 knockdown mice, the expression of innate immunity related cytokines were dysregulated at both E14.5 fetal brain and adult cortex. Sarm1 knockdown also resulted in brain size reduction and caused autistic-like behaviors, including cognitive inflexibility, impaired associative learning and reduced social interaction. In addition to neuronal morphogenesis, Sarm1 also modulated synaptic plasticity. Sarm1 knockdown mice had severe deficits in mGluR-dependent LTD but enhanced NMDA receptor-dependent LTP in hippocampal CA1. The protein composition of post-synaptic density was also altered in Sarm1 knockdown mice, suggesting its role in maintaining synaptic homeostasis. Applying the positive allosteric modulator of mGluR5, CDPPB, can restore both LTD defects and autistic-like behaviors. These results suggest significance of mGluR5 mediating responses in Sarm1 knockdown mice and echo the mGluR theory in the etiology of autism. In conclusion, our study demonstrates a role of Sarm1 in the neuronal innate immunity, neuronal morphogenesis and synaptic plasticity. Through these regulations, Sarm1 knockdown causes autistic-like behaviors in mouse.

中文摘要 III
ABSTRACT IV
INTRODUCTION 1
1. Brain development and autism 1
2. Innate immunity and brain development 4
3. Sarm1 is an evolutionary conserved protein containing multiple protein interaction motifs 6
4. The role of Sarm1 in innate immune system 7
5. The role of Sarm1 in neuron 8
SPECIFIC AIMS 11
Material and method 12
1. Immunohistochemistry 12
2. Brain anatomic analysis 13
3. Western blot analysis 14
4. Quantitative RT-PCR 14
5. Generation of Sarm1 knockdown transgenic mice 16
6. Animals and behavior assays 17
7. Electrophysiology 23
8. Antibodies 25
9. Calcium imaging 27
10. Data and statistical analyses 27
RESULTS 28
1. General characterization of Sarm1 28
2. Generation of Sarm1 miRNA knockdown transgenic mouse model 31
3. Reduction of Sarm1 dysregulates cytokine expression in brain 32
4. Sarm1 knockdown affects brain development 34
5. Sarm1 knockdown express autistic-like behaviors 36
6. Sarml knockdown leads to hypersynaptic responses upon glutamate Stimulation 40
7. Sarm1 knockdown disturbs synaptic plasticity 41
8. Behavior impairment in Sarm1 knockdown mice can be rescued by mGluR5 activation 44
Discussions 45
1. Neuroinflammation in ASD 45
2. The mechanism of Sarm1 in regulating synaptic plasticity 456
3. Different function of Sarm1 in different cell compartment or brain region …48
4. Interaction between prenatal immune activation and Sarm1 deficiency in brain brain development disorders 49
Reference 52
Figures and legend 59

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