VIP中间神经元失抑制效应在MCD痫性放电自限性受损中的作用机制

项目名称： VIP中间神经元失抑制效应在MCD痫性放电自限性受损中的作用机制

项目编号： No.81471321

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 杨辉

作者单位： 中国人民解放军第三军医大学

项目金额： 80万元

中文摘要： 大脑皮质发育障碍（MCD）是药物难治性癫痫的首要病因。临床数据证实MCD癫痫具有更长的发作时程，表明痫性放电自限性受损，MCD脑区抑制性神经环路的构架和/或功能存在异常。新近发现表达血管活性肠肽（VIP）的中间神经元负责接受兴奋性输入，并特征性地抑制表达生长抑素（SST）的中间神经元，进而使兴奋性神经元接受的抑制减弱。有趣的是，我们前期研究发现MCD脑区VIP中间神经元比例高于正常皮层。鉴于VIP中间神经元在抑制性神经环路中发挥核心作用，我们推测异构神经元放电→VIP中间神经元活化→SST中间神经元抑制→异构神经元失抑制→痫性放电自限性受损。为此，本课题拟以VIP中间神经元为切入点，利用MCD临床标本和动物模型，采用转基因动物、钙成像、双通道膜片钳等手段，从细胞和分子水平探讨VIP中间神经元介导的失抑制效应在MCD痫性放电调控中作用机制，进一步深化我们对MCD所致癫痫难治性的理解。

中文关键词： 皮质发育障碍；难治性癫痫；失抑制效应；中间神经元；血管活性肠肽

英文摘要： Malformation of cortical development (MCD) represents a well-recognized cause of intractable epilepsy. Clinical studies show that seizure duration induced by MCD is longer than other causes,suggesting an impaired self-limited capability of discharge.It also implies an abnormal structure and/or function in inhibitory neural circuit.More recent stuty revealed that vasoactive intestinal peptide-expressing (VIP) interneuron received the strongest excitation from long-range excitatory projection,and specialized in inhibiting Sst inhibitory neurons,resulted to a disinhibitory control to excitatoty circuit. It's interesting that our previous result showed the proportion of VIP interneuron in MCD lesion region is higher than that in normal cortex.Based on the evidence that VIP interneuron plays a central role in inhibitory neural circuit, we supposed a mechanism as discharge of malformed cells→activation of VIP interneuron →inhibition of SST interneuron→disinhibitory control of malformed cells→impaired self-limited capability of discharge.To address these concerns, in the present project, we employed the MCD patient sample and animal models, using transgene mice, calcium image and double-patch clamp, to elucidate the role and mechanism of disinhibitory control of VIP-expressing interneurons in self-limited suizure in MCD.The results may be helpful for us to better understanding of the refractory of MCD epilepsy.

英文关键词： MCD;intractable epilepsy;disinhibitory control;interneuron;VIP