來自清華大學(xué)生命科學(xué)學(xué)院和冷泉港實驗室的研究人員在近期發(fā)表的文章中解析了一種重要的精神分裂癥易感基因的作用機制，有助于解析神經(jīng)遞質(zhì)作用機理,，這一研究成果公布在《美國國家科學(xué)院院刊》（PNAS）雜志上,。
在這篇文章中，研究人員發(fā)現(xiàn)一個精神分裂癥單易感基因：dysbindin能通過兩個獨立的機制,，分別調(diào)控谷氨酸和多巴胺功能,，從而導(dǎo)致兩種臨床相關(guān)的行為表型。dysbindin（dystrobrevin-binding protein）,，即短棒菌素結(jié)合蛋白基因,，這一基因于2002年被報道，稱其多態(tài)性與精神分裂癥有關(guān),，之前的研究表明這一基因能影響谷氨酸和多巴胺功能,，并引起脊椎動物和無脊椎動物的臨床相關(guān)行為。在這一基礎(chǔ)上,，研究人員又發(fā)現(xiàn)減少果蠅突觸前神經(jīng)元中dysbindin基因的表達量,，會大幅抑制谷氨酸突觸遞質(zhì)，而這種谷氨酸缺失會導(dǎo)致記憶受損,。
但是神經(jīng)膠質(zhì)細胞中這一基因表達量降低,，則會引起高多巴胺活性，從而引起異常運動,，以及交配改變,。這些數(shù)據(jù)說明，dysbindin基因能調(diào)控谷氨酸神經(jīng)功能,，以及多巴胺代謝,。
近期來自安徽醫(yī)科大學(xué)等處的研究人員還新發(fā)現(xiàn)一個新精神分裂癥易感基因，他們通過全基因組關(guān)聯(lián)研究平臺和生物信息分析技術(shù),，對近12000例患者和正常對照人群的全基因組關(guān)聯(lián)研究,，結(jié)果在11號染色體上發(fā)現(xiàn)了一個新的精神分裂癥易感基因TSPAN18，同時驗證了國外既往研究發(fā)現(xiàn)的位于6號染色體上的易感基因,。
文章的通訊作者是鐘毅教授,，其早年畢業(yè)于清華大學(xué)工程物理系，于美國愛荷華大學(xué)獲得博士學(xué)位,，1992年受聘到美國冷泉港實驗室,，2001年被聘為清華大學(xué)生物系講座教授，博士生導(dǎo)師,。同年被聘為教育部長江計劃特聘教授,。
神經(jīng)遞質(zhì)（neurotransmitter）是指在神經(jīng)元的突觸前膜向突觸后膜起信息傳遞作用的化學(xué)物質(zhì)，又稱神經(jīng)介質(zhì)神經(jīng)系統(tǒng)傳遞信息,，是從各種神經(jīng)元軸突末端釋放一定的神經(jīng)遞質(zhì),，該遞質(zhì)通過突觸間隙作用于突觸后膜,，產(chǎn)生突觸后電位，引起下一級神經(jīng)元的應(yīng)答活動,。這種通過神經(jīng)遞質(zhì)的化學(xué)傳遞是突觸傳遞的基本形式,。研究發(fā)現(xiàn)多神經(jīng)遞質(zhì)系統(tǒng)的失調(diào)是許多精神疾病的重要病理生理特征，其中尤其是精神分裂癥表現(xiàn)明顯,。但是至今科學(xué)家們對于其中的機制了解的還并不多,。
doi:10.1073/pnas.1114569108
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Schizophrenia susceptibility gene dysbindin regulates glutamatergic and dopaminergic functions via distinctive mechanisms in Drosophila
Lisha Shao Yichun Shuai Jie Wang Shanxi Feng Binyan Lu Zuo Li Yukai Zhao Lianzhang Wang and Yi Zhong
The dysfunction of multiple neurotransmitter systems is a striking pathophysiological feature of many mental disorders, schizophrenia in particular, but delineating the underlying mechanisms has been challenging. Here we show that manipulation of a single schizophrenia susceptibility gene, dysbindin, is capable of regulating both glutamatergic and dopaminergic functions through two independent mechanisms, consequently leading to two categories of clinically relevant behavioral phenotypes. Dysbindin has been reported to affect glutamatergic and dopaminergic functions as well as a range of clinically relevant behaviors in vertebrates and invertebrates but has been thought to have a mainly neuronal origin. We find that reduced expression of Drosophila dysbindin (Ddysb) in presynaptic neurons significantly suppresses glutamatergic synaptic transmission and that this glutamatergic defect is responsible for impaired memory. However, only the reduced expression of Ddysb in glial cells is the cause of hyperdopaminergic activities that lead to abnormal locomotion and altered mating orientation. This effect is attributable to the altered expression of a dopamine metabolic enzyme, Ebony, in glial cells. Thus, Ddysb regulates glutamatergic transmission through its neuronal function and regulates dopamine metabolism by regulating Ebony expression in glial cells.
