PLoS Bio：舒友生等发现癫痫条件下长时程抑制性信号的增强

图注：图中背景为药物难治性癫痫患者（伴胶质瘤，颞叶亮白色部位）的脑冠状面MRI图片。白色曲线为FS神经元的膜电位变化，一串动作电位后伴随有自发突触后电位（由非同步化GABA释放引起）。图中卡通显示：与非癫痫（Non-Epileptic）组织相比，癫痫（Epileptic）组织中FS神经元的传出突触上非同步化释放增加。

5月8日，国际著名杂志PLoS Biology在线发表了上海生科院神经所研究人员的最新研究成果“Enhancement of asynchronous release from fast-spiking interneuron in human and rat epileptic neocortex，”，文章中，研究者发现了癫痫条件下长时程抑制性信号的增强现象。

兴奋性和抑制性信号的平衡是大脑发挥正常功能的关键。打破这一平衡将可能导致癫痫等神经系统疾病。一般认为，抑制性GABA系统的功能下调直接导致了神经网络的强烈兴奋和癫痫放电。中科院神经所舒友生研究组发现了在癫痫条件下抑制性系统的新变化，即快发放中间神经元（FS）的非同步化GABA释放在癫痫组织中被显著性增强，并对其机制进行了探讨。该工作主要由博士研究生江漫等完成，是与复旦大学华山医院的王开颜博士和同济大学曲阳医院的郭辉博士的合作成果。

神经递质的释放一般都是和动作电位紧密偶联（即同步化释放）；然而，高频发放动作电位后，在同步化释放之后还会有长时间的非同步化释放。为了揭示癫痫发生的机制，以往的研究主要集中在同步化GABA释放的改变。由于癫痫条件下神经元的膜电位会强烈去极化并伴随高频动作电位的发放，因此研究神经元高频发放情况下非同步化GABA释放的变化及其机制非常重要。江漫等在药物难治性癫痫患者和癫痫动物模型的离体脑薄片上采用膜片钳技术记录FS神经元和锥体细胞（PC），发现人类和大鼠皮层中非同步化释放广泛存在于FS神经元的所有突触中，其中FS神经元的自突触（支配自身的突触）比FS神经元到PC的突触具有更强的非同步化释放。更重要的是，非同步化释放的强度在癫痫组织中被显著增强。非同步化GABA释放的增强可能是癫痫大脑中皮层中间神经元针对过度兴奋的一种应答，为癫痫条件下的神经网络提供更强的长时程抑制信号，进而改变网络的电活动。进一步的实验显示动作电位在癫痫情况下的幅度增加是非同步化释放增强的可能机制。

该工作得到了中国科学院、科技部、国家自然科学基金委、上海市科委和国家重点实验室等项目的资助。（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.