中研院研究揭開自閉症的成因,原來是突變基因導致腦部特定神經迴路異常;研究也證實,治療肺結核的抗生素,可以彌補突變基因帶來的問題,能有效改善患類自閉症小鼠的異常行為,未來可望用於臨床治療。

全世界約有6000多萬人患自閉症,台灣約1萬多人,平均每50名兒童就有一人罹患自閉症,但自閉症的成因不明,海外曾有研究指出自閉症與孕婦、兒童攝入塑化劑有關。

中研院研究員薛一蘋和研究團隊鑽研基因TBR1分子多年,他們在小鼠實驗中發現,專門控制大腦皮質和杏仁核的TBR1一旦突變,會讓小鼠缺少連接左右腦杏仁核的神經迴路「後段前連合」,導致訊息無法正常傳遞。

由於杏仁核掌控社交活動、情緒反應等,TBR1異常的小鼠,出現類似自閉症的行為。

研究也發現,TBR1控制其他15個自閉症致病基因,這群基因利用相似的方式,左右腦部認知和社交行為。

薛一蘋表示,雖然TBR1突變,造成神經用來溝通的「離子通道」數量少、無法改變,但治療肺結核的抗生素「D-環絲胺酸」可以提升離子通道的活性,改善病情;自閉鼠注射此抗生素後,行為變得和正常鼠差不多。

過去只知自閉症源於早期神經發育異常,但卻不清楚是哪一特定神經迴路,因此這項突破性的研究成果,一刊登到國際頂尖期刊「自然神經科學」(Nature Neuroscience),許多科學家都搶著要看報告。



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Nature Neuroscience (19 January 2014) | doi:10.1038/nn.3626

 

Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality

Tzyy-Nan Huang , Hsiu-Chun Chuang , Wen-Hsi Chou , Chiung-Ya Chen , Hsiao-Fang Wang , Shen-Ju Chou & Yi-Ping Hsueh

 

The neuron-specific transcription factor T-box brain 1 (TBR1) regulates brain development. Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs). Here, we show that Tbr1 haploinsufficiency results in defective axonal projections of amygdalar neurons and the impairment of social interaction, ultrasonic vocalization, associative memory and cognitive flexibility in mice. Loss of a copy of the Tbr1 gene altered the expression of Ntng1, Cntn2 and Cdh8 and reduced both inter- and intra-amygdalar connections. These developmental defects likely impair neuronal activation upon behavioral stimulation, which is indicated by fewer c-FOS–positive neurons and lack of GRIN2B induction in Tbr1+/|[minus]| amygdalae. We also show that upregulation of amygdalar neuronal activity by local infusion of a partial NMDA receptor agonist, d-cycloserine, ameliorates the behavioral defects of Tbr1+/|[minus]| mice. Our study suggests that TBR1 is important in the regulation of amygdalar axonal connections and cognition.

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