臺灣博碩士論文加值系統

　　Dravet症候群是發生於嬰兒時期的癲癇疾病，同時伴隨著心智發展遲緩以及自閉症的產生。目前已知絕大多數的Dravet症候群病患是因為Scn1a基因突變導致第一型鈉離子通道 (Nav1.1) 異常。幼兒患有Dravet症候群會有嚴重的視覺知覺能力及空間記憶能力低下，其中空間記憶能力與海馬迴的神經新生有著很大的關聯性，然而Scn1a基因與神經新生的調控仍是未知，因此我們建立一個帶有人類Scn1a基因突變點的Dravet小鼠 (Scn1a1099X/+)，此小鼠具有自發性癲癇以及對熱誘發癲癇的表徵，與Dravet症候群病人的症狀相符。因此本篇論文使用一天大 (postnatal day 1, PD1) 及八天大 (postnatal day 8, PD8) Dravet小鼠進行體外神經幹細胞球培養，藉由分析其形成神經球數量以及免疫細胞染色探討神經幹細胞增生的能力，同時將神經球進行分化再用免疫細胞染色探討神經幹細胞分化能力。實驗結果顯示Scn1a基因轉殖鼠所培養出的神經幹細胞球的數目會增加，此神經幹細胞球的數目增加是藉由細胞增生指標Ki67增加所導致，此外也發現神經幹細胞指標GAFP細胞增加以及細胞內鈣離子濃度增加。神經幹細胞除了具有增生的能力外，也具有分化成神經、星形膠質細胞以及寡突膠細胞的能力，將神經幹細胞球分化5天後發現DCX+神經細胞在PD1會增加，而Tuj1+神經細胞在則PD1及PD8皆上升，同時發現CNPase+寡突膠細胞在PD8會下降。進一步的將細胞分化15天後會發現MAP2+神經細胞數會增加，且些神經細胞中有80%會分化成GAD67+抑制性神經元。過去已知GABA會調控神經新生，因此進一步探討GABA對Scn1a基因缺陷的神經幹細胞影響，結果顯示GABA會促進PD1神經幹細胞球的形成，但抑制PD8神經幹細胞球形成，進一步將神經幹細胞球分化五天後，可抑制Scn1a基因缺陷後的異常神經分化。綜合上述結果發現Scn1a基因缺陷後會加速神經幹細胞分化成神經細胞，顯示Scn1a基因會調控神經新生。

Dravet syndrome is a refractory seizure characterized by severe infant-onset myoclonic epilepsy, delayed psychomotor development and autism-spectrum behaviours. Loss-of-function mutations in Scn1a gene which encodes the type Ⅰvoltage-gated sodium channel (Nav1.1) is the predominant molecular cause in most patients. Children with Dravet syndrome are significantly impaired in visuo-perceptual skill performance, and the spatial memory have been reported close relative to hippocampus neurogenesis. However, the underlying dysfunction of the Scn1a gene might confer to the brain neurogenesis is largely unknown. Here, we constructed a transgenic mice with Scn1a1099X knock-in (KI) allele which presented an animal model of Dravet syndrome, exhibited spontaneous epileptic discharges and susceptible to hyperthermia-induced seizures. Our results show that Nav1.1 deficiency lead to significant increase in neural stem cell-derived neurospheres number and accompanied with increasing neural stem cell (NSC) marker, GFAP. Quantification of cell division with the proliferation indicator, Ki67 or PCNA, showed that cell proliferation was significant increase result from Nav1.1 dysfunction. Measurement of [Ca2+]i by fura-2 AM Ca2+ imaging demonstrated that [Ca2+]i was markedly elevated in neurospheres derived from Scn1a mutation mice. NSC are characterized as cells with potential to produce a large amount of progeny that grow and differentiate into neuron, astrocyte and oligodendrocyte. Immunocytochemistry result indicated that loss of Nav1.1 in NSC result in significant increase the neuroblast and immature neuron but oligodendrocyte in neurosphere-derived cells which isolated from postnatal day 1 mice. In contrast, NSC obtained from postnatal day 8 Scn1a-deficit animal showed an upregulation of immature neuron and oligodendrocyte lineage but neuroblast. Moreover, prolonged differentiation for 2 weeks of neurosphere-derived cell culture isolated from postnatal day 1 Scn1a-mutant mice revealed that the ratio of mature neuron and GABAergic neuron were dramatically increased. GABA has been known to regulate neurogenesis, thus we further to investigate the effects of GABA on Scn1a deficiency neurosphere. Our results show that GABA promote neurosphere formation in PD1 neurosphere, but inhibit neurosphere formation in PD8 neurosphere. When neurosphere were induced to differentiation for 5 days, we found abnormal neuronal differentiation were reverse by GABA. These results revealed that loss of Scn1a gene might contribute to promote NSCs differentiate into neuronal series. Our results support that Scn1a gene play an important role in postnatal neuronal development.

摘要 II
Abstract IV
圖目錄 VI
表目錄 VII
縮寫表 VIII
第一章 緒論 (Introduction) 1
第一節　Dravet症候群 1
第二節 鈉離子通道簡介 2
第三節　Dravet症候群之動物模式研究 3
第四節 異常神經新生與癲癇及行為模式改變之關係 4
第五節 神經新生之調控 5
第六節 研究動機與目的 6
第二章 實驗材料與方法 (Materials and Methods) 8
第一節 實驗動物 8
第二節 神經幹細胞培養 8
第三節 神經幹細胞分化 9
第四節 免疫細胞染色法 (Immunocytochemistry) 9
第五節 西方點墨法 (Western blot) 10
第六節 活細胞鈣離子濃度測定 10
第七節 統計分析 10
第三章 結果 (Result) 11
第一節　Nav1.1表達在神經幹細胞 11
第二節 Scn1a缺陷會造成神經幹細胞增生 12
第三節　Scn1a突變後會造成細胞內鈣離子濃度增加 13
第四節 Scn1a缺陷後會促使幹細胞分化成神經細胞 14
第五節　Scn1a缺陷會促使神經幹細胞分化成抑制性神經元 16
第六節 TTX抑制神經幹細胞之增生，但促進其分化成神經細胞 16
第七節 GABA可抑制Scn1a缺陷後造成的神經新生 17
第四章 討論 (Discussion) 20
第一節 總述 20
第二節　鈉離子通道調控神經幹細胞之增生與分化 20
第三節　鈣離子訊息傳遞路徑調控神經新生 23
第四節 GABA調控神經新生 24
第五節 未來展望 25
第五章 圖表 (Figures) 27
參考文獻 (References) 67

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