上海交大特別研究員、Bio-X研究院李衛(wèi)東博士與美國加州大學(xué)洛杉磯分校,、約翰霍普金斯大學(xué)等校合作,，日前在《Cell》子刊、神經(jīng)科學(xué)頂級期刊《Neuron》雜志上發(fā)表學(xué)術(shù)論文,，揭示精神分裂癥的基因?qū)θ舜竽X的影響機(jī)制,。這一發(fā)現(xiàn)將為醫(yī)學(xué)界通過基因治療，改善大腦特殊區(qū)域基因缺失引發(fā)的認(rèn)知和情感障礙提供一種新的途徑,。
精神分裂癥是最嚴(yán)重的精神疾病,，病因迄今尚未闡明。遺傳因素被視為最主要的致病因素,。其中,，Disrupted-in-Schizophrenia-1（DISC1）基因被認(rèn)為是當(dāng)今最有價(jià)值的精神分裂癥及抑郁癥等精神疾病的易感基因之一。
DISC1基因最早發(fā)現(xiàn)于一個(gè)蘇格蘭家族,，其第1號染色體和第11號染色體的染色體異常易位,，凡攜帶者絕大多數(shù)發(fā)展成為精神分裂癥、抑郁癥、躁郁癥等精神疾病患者,。DISC1基因成為迄今發(fā)現(xiàn)的與精神疾病關(guān)聯(lián)的第一個(gè)明確的變異基因,。
科學(xué)家們普遍認(rèn)為，大腦早期發(fā)育過程中的異常,，是引發(fā)精神分裂癥等神經(jīng)發(fā)育障礙疾病的最主要原因之一,，相當(dāng)一部分患者是在成年期或老年期發(fā)病。哺乳動物中樞神經(jīng)系統(tǒng)的發(fā)育主要發(fā)生在孕幼期,，但特定大腦區(qū)域如海馬齒狀回卻存在終身保持旺盛的神經(jīng)元再生現(xiàn)象,。這種成年期神經(jīng)新生過程在學(xué)習(xí)、認(rèn)知及神經(jīng)精神疾病中的作用越來越受到科學(xué)家們的關(guān)注,。
李衛(wèi)東研究組主要研究方向之一就是利用DISC1等基因工程小鼠及shRNA病毒載體腦區(qū)定位注射實(shí)驗(yàn),，研究精神分裂癥及抑郁癥發(fā)病機(jī)理。在此前基礎(chǔ)上,，研究組發(fā)現(xiàn)在成年后的海馬齒狀回(dentate gyrus,，DG)新生神經(jīng)元中，特異性敲除DISC1基因,，能刺激mTOR信號通路,，使神經(jīng)元過度興奮，出現(xiàn)神經(jīng)形態(tài)學(xué)缺陷,。非常重要的是,，這一基因操作可影響約500個(gè)新生神經(jīng)元,，恰恰是這500個(gè)新生神經(jīng)元的異常竟然導(dǎo)致了認(rèn)知和情感出現(xiàn)明顯障礙,。當(dāng)這群新生神經(jīng)元提前被抑制時(shí)，認(rèn)知行為缺陷就得以逆轉(zhuǎn),。如果利用一種FDA批準(zhǔn)的抑制劑處理,，則可糾正mTOR信號途徑的不良反應(yīng)，預(yù)防和治療這種行為缺陷,。
李衛(wèi)東曾表示：“DISC1基因編碼充當(dāng)新生神經(jīng)細(xì)胞的‘音樂指揮棒’,，指導(dǎo)新細(xì)胞達(dá)到適當(dāng)?shù)奈恢茫顾鼈兺昝赖卣先胍延械膹?fù)雜神經(jīng)系統(tǒng)中,。如果DISC1蛋白不能正常工作,，那么新神經(jīng)元也許不能正常融入已有的神經(jīng)網(wǎng)路‘大家庭’。”這項(xiàng)最新研究發(fā)現(xiàn),，針對成年期神經(jīng)元發(fā)育異常的治療,，也許能產(chǎn)生顯著療效。
加州大學(xué)洛杉磯分校Silva教授為該文共同通訊作者,，參與這項(xiàng)研究的還包括約翰霍普金斯大學(xué)醫(yī)學(xué)院的宋紅軍教授和明國莉教授,，以及上海交通大學(xué)Bio-X研究院賀林院士等。（生物谷Bioon.com）
doi:10.1016/j.neuron.2012.12.033
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mTOR Inhibition Ameliorates Cognitive and Affective Deficits Caused by Disc1 Knockdown in Adult-Born Dentate Granule Neurons
Miou Zhou1, 10, Weidong Li1, 2, 3, 10, , , Shan Huang1, Juan Song6, 7, 8, Ju Young Kim6, 7, Xiaoli Tian4, Eunchai Kang6, 7, Yoshitake Sano1, Cindy Liu6, 7, J. Balaji1, Shumin Wu5, Yu Zhou1, 9, Ying Zhou2, 3, Sherveen N. Parivash1, Dan Ehninger1, 11, Lin He2, Hongjun Song6, 7, 8, Guo-li Ming6, 7, Alcino J. Silva1,
Abnormalities during brain development are thought to cause psychiatric illness and other neurodevelopmental disorders. However, developmental processes such as neurogenesis continue in restricted brain regions of adults, and disruptions of these processes could contribute to the phenotypes of neurodevelopmental disorders. As previously reported, we show that Disc1 knockdown specifically in adult-born dentate gyrus (DG) neurons results in increased mTOR signaling, hyperexcitability, and neuronal structure deficits. Disc1 knockdown also resulted in pronounced cognitive and affective deficits, which could be reversed when the affected DG neurons were inactivated. Importantly, reversing increases in mTOR signaling with an FDA-approved inhibitor both prevented and treated these behavioral deficits, even when associated structural deficits were not reversed. Our findings suggest that a component of the affective and cognitive phenotypes in neurodevelopmental disorders may be caused by disruptions in adult-born neurons. Consequently, treatments directed at this cell population may have a significant impact on these phenotypes.
