星形胶质细胞源性的IL-21通过LCN2调控神经元兴奋性在颞叶癫痫中的作用机制

The interaction between astrocytes and neurons has become a hot spot in epilepsy research.However, the precise mechanism of regulating the excitability of neurons is still unclear.It has been proved that the transformation of astrocyte phenotype (type /A2 A1) plays an important role in the regulation of neuronal excitability.Our previous studies showed that IL-21 was mainly expressed in astrocytes of temporal lobe epilepsy.Further pre experimental findings showed that IL-21 was mainly expressed in LCN2 co labeled astrocytes.It can enhance seizure sensitivity.Since LCN2 is an important marker of A1 type astrocytes and it is also an important factor leading to neuronal excitability.It is showed that Astrocyte derived IL-21 affects the transformation of cell phenotype.It controlls LCN2 Which affects the excitability of neurons and caused Temporal lobe epilepsy finally.Therefore, this project uses IL-21 conditional knockout mice model of epilepsy,using the technologies of in vivo multiple conductivity physiology, molecular biology and cell co culture to investigate the effect of astrocyte derived IL-21 on regulation of A1 cell LCN2 and how to increased neuronal excitability and the mechanism of epilepsy.This study not only can explain the pathogenesis of intractable epilepsy, but also provides a new way for the treatment of intractable epilepsy.

星形胶质细胞与神经元之间相互调控成为癫痫研究热点，但其调控神经元兴奋性的精确机制仍不清楚。研究证实星形胶质细胞表型的转化（A1型/A2型）在调控神经元兴奋性中具有重要作用。我们前期研究显示IL-21主要表达于颞叶癫痫组织星形胶质细胞，进一步预实验发现，IL-21主要表达于脂质运载蛋白2(LCN2)共标的星形胶质细胞,可以增强癫痫发作敏感性。鉴于LCN2是A1型星形胶质细胞的重要标志，是导致神经元兴奋性的重要因素,据此推测：星形胶质细胞源性的IL-21影响了细胞自身表型转化，通过调控LCN2，影响神经元的兴奋性，最终导致颞叶癫痫发作。因此，本项目运用IL-21条件性敲除小鼠癫痫模型，采用在体多导电生理、细胞共培养等技术，探讨星形胶质细胞源性的IL-21通过调控A1型细胞LCN2,从而增加神经元兴奋性，导致癫痫发作的机制。该研究不仅阐明难治性癫痫的发病机制，同时为难治性癫痫的治疗提供新靶点。