异构神经元在皮质发育障碍痫样放电扩散传播中的作用机制研究

It was revealed that the heterogeneous neurons(HNs) was a kind of spontaneous seizure cells in the lesions of malformations of cortical development (MCD),but the mechanism for seizure spreading remains unclear.As HNs without synapes contact with the other cells in the lesions of MCD,and our studies found HNs over-expressed IL-6, also the high content of IL-6 and soluble IL-6 receptor(sIL-6R) in the serum, the cerebro-spinal fluid and the specimen of the patients with MCD,and the fact that the other neurons did not express sIL-6R, so we think that IL-6 secreted by HNs mediated the trans-signaling by sIL-6R to excite neurons directly;or induced glial cells to secrete excitatory neurotransmitter to make the neurons product action potential indirectly. Here we presumed the HNs in the lesion of MCD mediated the seizure spreading by trans-signaling. Based on these, in this study, we plan to explore the relation between the molecular and cells related to trans-signaling and seizure spreading in the lesion of MCD by neuro-electrophysiological, intracellular calcium imaging of brain slice, molecular biology techniques to clarify the mechanisms for the seizure spreading of MCD, which has important theoretical and practical value in depth understanding of MCD.

研究表明，异构神经元（HNs）是皮质发育障碍（MCD）内具有自发性痫样放电的致痫细胞，但其痫样放电传播的作用机制仍不清楚。鉴于HNs与MCD内其他神经细胞间缺乏突触等结构的特点，和我们的前期研究发现HNs高表达IL-6，且MCD患者的血浆、脑脊液和MCD标本中的IL-6和可溶性IL-6受体（sIL-6R）含量显著升高，但参与MCD内痫样同步放电的其他神经元并不表达IL-6R的事实，我们认为HNs分泌的IL-6可能通过sIL-6R介导的跨信号转导作用，直接诱导神经元兴奋；或通过诱导胶质细胞分泌兴奋性递质，间接引起神经元同步放电。而提出HNs 通过跨信号转导作用介导MCD痫样放电扩散的假设。本项目针对此假设，运用神经电生理、脑片胞内钙成像、分子生物学等技术，探讨参与跨信号转导的相关分子和细胞与MCD痫样放电传播的关系，阐明MCD痫样放电的传播机制，对深入认识MCD具有重要的理论意义和实践价值。

皮质发育障碍（MCD）是儿童药物难治性癫痫的重要病因，但MCD病灶内痫样放电扩散传播的作用机制仍不清楚。我们在前期研究的基础上，提出了MCD内异构神经元（HNs）分泌的IL-6可能通过sIL-6R介导的跨信号转导作用导致了痫样放电扩散传播的假设。针对此假设，本研究以MCD动物模型为研究对象，运用神经电生理、分子生物学等技术，对以下内容进行了研究：1）IL-6在MCD中的表达及分布；2）IL-6介导的跨信号转导作用对MCD痫样放电的影响；3）阻断IL-6介导的跨信号转导作用对MCD痫样放电的影响。在成功建立了两种MCD动物模型后研究发现：IL-6、IL-6R、gp130在鼠脑皮层组织中主要高表达于HNs；IL-6对MCD模型鼠痫性放电阈值、放电持续时间有影响，这种作用能够被sgp130Fc减弱。这些结果表明： IL-6参与了MCD形成和痫样放电的扩散传播有关，而IL-6的这种作用是通过sIL-6R介导的跨信号转导作用来实现的，假设被证实。本研究为将来针对IL-6/sIL-6R 这一治疗靶点控制MCD所致癫痫的发作具有潜在的应用价值。