圖注：圖中背景為藥物難治性癲癇患者（伴膠質(zhì)瘤,，顳葉亮白色部位）的腦冠狀面MRI圖片,。白色曲線為FS神經(jīng)元的膜電位變化,，一串動作電位后伴隨有自發(fā)突觸后電位（由非同步化GABA釋放引起）。圖中卡通顯示：與非癲癇（Non-Epileptic）組織相比,，癲癇（Epileptic）組織中FS神經(jīng)元的傳出突觸上非同步化釋放增加,。
5月8日，國際著名雜志PLoS Biology在線發(fā)表了上海生科院神經(jīng)所研究人員的最新研究成果“Enhancement of asynchronous release from fast-spiking interneuron in human and rat epileptic neocortex,，”,，文章中，研究者發(fā)現(xiàn)了癲癇條件下長時(shí)程抑制性信號的增強(qiáng)現(xiàn)象,。
興奮性和抑制性信號的平衡是大腦發(fā)揮正常功能的關(guān)鍵,。打破這一平衡將可能導(dǎo)致癲癇等神經(jīng)系統(tǒng)疾病。一般認(rèn)為,，抑制性GABA系統(tǒng)的功能下調(diào)直接導(dǎo)致了神經(jīng)網(wǎng)絡(luò)的強(qiáng)烈興奮和癲癇放電,。中科院神經(jīng)所舒友生研究組發(fā)現(xiàn)了在癲癇條件下抑制性系統(tǒng)的新變化，即快發(fā)放中間神經(jīng)元（FS）的非同步化GABA釋放在癲癇組織中被顯著性增強(qiáng),，并對其機(jī)制進(jìn)行了探討,。該工作主要由博士研究生江漫等完成，是與復(fù)旦大學(xué)華山醫(yī)院的王開顏博士和同濟(jì)大學(xué)曲陽醫(yī)院的郭輝博士的合作成果,。
神經(jīng)遞質(zhì)的釋放一般都是和動作電位緊密偶聯(lián)（即同步化釋放）,；然而，高頻發(fā)放動作電位后,，在同步化釋放之后還會有長時(shí)間的非同步化釋放,。為了揭示癲癇發(fā)生的機(jī)制，以往的研究主要集中在同步化GABA釋放的改變,。由于癲癇條件下神經(jīng)元的膜電位會強(qiáng)烈去極化并伴隨高頻動作電位的發(fā)放,，因此研究神經(jīng)元高頻發(fā)放情況下非同步化GABA釋放的變化及其機(jī)制非常重要。江漫等在藥物難治性癲癇患者和癲癇動物模型的離體腦薄片上采用膜片鉗技術(shù)記錄FS神經(jīng)元和錐體細(xì)胞（PC）,，發(fā)現(xiàn)人類和大鼠皮層中非同步化釋放廣泛存在于FS神經(jīng)元的所有突觸中,，其中FS神經(jīng)元的自突觸（支配自身的突觸）比FS神經(jīng)元到PC的突觸具有更強(qiáng)的非同步化釋放,。更重要的是，非同步化釋放的強(qiáng)度在癲癇組織中被顯著增強(qiáng),。非同步化GABA釋放的增強(qiáng)可能是癲癇大腦中皮層中間神經(jīng)元針對過度興奮的一種應(yīng)答,，為癲癇條件下的神經(jīng)網(wǎng)絡(luò)提供更強(qiáng)的長時(shí)程抑制信號，進(jìn)而改變網(wǎng)絡(luò)的電活動,。進(jìn)一步的實(shí)驗(yàn)顯示動作電位在癲癇情況下的幅度增加是非同步化釋放增強(qiáng)的可能機(jī)制,。
該工作得到了中國科學(xué)院、科技部,、國家自然科學(xué)基金委,、上海市科委和國家重點(diǎn)實(shí)驗(yàn)室等項(xiàng)目的資助。（生物谷Bioon.com）
doi:10.1371/journal.pbio.1001324
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Enhancement of Asynchronous Release from Fast-Spiking Interneuron in Human and Rat Epileptic Neocortex
Man Jiang1, Jie Zhu1, Yaping Liu1, Mingpo Yang1, Cuiping Tian1, Shan Jiang1, Yonghong Wang1, Hui Guo2, Kaiyan Wang3*, Yousheng Shu1*
Down-regulation of GABAergic inhibition may result in the generation of epileptiform activities. Besides spike-triggered synchronous GABA release, changes in asynchronous release (AR) following high-frequency discharges may further regulate epileptiform activities. In brain slices obtained from surgically removed human neocortical tissues of patients with intractable epilepsy and brain tumor, we found that AR occurred at GABAergic output synapses of fast-spiking (FS) neurons and its strength depended on the type of connections, with FS autapses showing the strongest AR. In addition, we found that AR depended on residual Ca2+ at presynaptic terminals but was independent of postsynaptic firing. Furthermore, AR at FS autapses was markedly elevated in human epileptic tissue as compared to non-epileptic tissue. In a rat model of epilepsy, we found similar elevation of AR at both FS autapses and synapses onto excitatory neurons. Further experiments and analysis showed that AR elevation in epileptic tissue may result from an increase in action potential amplitude in the FS neurons and elevation of residual Ca2+ concentration. Together, these results revealed that GABAergic AR occurred at both human and rat neocortex, and its elevation in epileptic tissue may contribute to the regulation of epileptiform activities.
