星形胶质细胞的Lrp4对癫痫发生的调控作用及其机制研究

癫痫是一种常见且严重的慢性神经疾病，已知癫痫持续状态可诱导癫痫的发生，然而其分子机制尚不明确。有研究表明星形胶质细胞和腺苷稳态对神经元活动及癫痫发生具有重要的调节作用，但是具体的机制仍不清晰。蛋白多糖agrin和它的受体-低密度脂蛋白相关蛋白-4（Lrp4）对于神经肌肉接头的发育、分化和维持必不可少。我们前期的研究发现：在大脑里Lrp4主要表达在海马的星形胶质细胞，敲除Lrp4提高胞外腺苷水平和降低兴奋性突触传递效率。另外，Lrp4还调节海马区兴奋性神经元自发放动作电位频率和对癫痫发作诱导的阈值。据此我们提出假说：Lrp4参与调节由癫痫持续状态诱导的癫痫发生。本项目拟在原创性的工作基础上分析agrin/Lrp4信号通路与癫痫发生的相关性，探讨其在癫痫发生过程中的功能和潜在机制。本研究将揭示星形胶质细胞Lrp4调控癫痫发生的新功能和机制，为临床治疗癫痫提供新的靶点。

Epilepsy is a common and serious neurological disorder. Although it is known that status epilepticus (SE) could induce epilepsy, the underlying molecular mechanisms remain to be elucidated. Accumulating evidence indicates a role of astrocytes and adenosine homeostasis in regulating neuronal activity and epilepsy development. However, underlying mechanisms are not well understood. Agrin and its receptor-low density lipoprotein receptor-related protein (Lrp4) are well known to be critical for the development, differentiation and maintenance of neuromuscular junction. In our previous studies, we first found that: Lrp4 was mostly expressed in astrocytes in the brain, deletion of which increased the extracellular level of adenosine and decreased excitatory synaptic strength. In addition, it modulated spontaneous firing frequency of excitatory neurons in the hippocampus and the threshold to SE. Based on these results, we raise our hypothesis: Lrp4 modulates epileptogenesis casued by SE. The present project will determine: (1) whether Lrp4 expression is regulated during epileptogenesis in vivo; (2) whether Lrp4 in astrocytes is critical for epileptogenesis; (3) what the underlying mechanisms are. Results may identify potential targets for development of preventive therapies.