调控AMIGO3对惊厥持续状态后未成熟脑海马异常神经环路的影响及其机制研究

Seizure is one of the most common critical diseases of the nervous system in children. Repeated and long-term seizure may lead to epileptogenesis and cognitive deficits. Recent researches found the formation of abnormal neural circuits after seizures in immature brain play an important role in epileptogenesis and cognitive deficits. However, there are no effective methods to prevent the occurrence and development of seizure-induced brain damages. Lingo-1 and AMIGO3, the members of the leucine rich repeat (LRR) family, are involved in lots of molecular interactions associated with the depression of axonal regeneration and remyelination. Our research group has found that down-regulation of Lingo-1 expression could improve seizure-induced brain damages and the up-regulation of Lingo-1 level was later than the occurrence of brain damages, while up-regulation of AMIGO3 mRNA level was prior to Lingo-1 mRNA expression increased after seizure, which indicated that AMIGO3 may be involved in brain damages in acute period after seizure. Therefore, this project intends to study the relationship of AMIGO3 and Lingo-1, the mechanism between AMIGO3 and abnormal neural circuits in different periods after seizures. And we will observe whether the abnormal neural circuits are improved through regulating the expression of AMIGO3, which provide a new way to effectively prevent and treat seizure-induced brain damages.

儿童期未成熟脑惊厥易感性高，且易导致惊厥性脑损伤。有效防治惊厥性脑损伤，减少癫痫、智力低下等后遗症一直是儿童神经学急需解决的热点问题。最新研究发现惊厥后海马异常神经环路形成是影响惊厥性脑损伤远期预后的主要因素，脑内Lingo-1和AMIGO3信号分子对神经轴突生长、髓鞘化等具有重要的调控作用。在课题组前期研究发现惊厥后Lingo-1参与海马神经轴突、髓鞘及突触结构和功能损伤病理过程，但其表达增加晚于神经损伤发生，而AMIGO3表达增加先于Lingo-1的基础上，进一步探讨惊厥后不同时期海马AMIGO3和Lingo-1表达的时序性关系及AMIGO3对海马神经环路（轴突、髓鞘、突触）结构和功能的影响，探讨AMIGO3是否通过调控下游ROCK/RhoA、EGFR/PI3K/AKT信号而发挥作用，观察调控AMIGO3表达能否改善惊厥所致海马神经环路损伤，为进一步有效防治惊厥性脑损伤提供新的途径。

最新研究发现惊厥后海马异常神经环路形成是影响惊厥性脑损伤远期预后的主要因素，脑内Lingo-1和AMIGO3信号分子对神经轴突生长、髓鞘化等具有重要的调控作用。在课题组前期研究发现惊厥后Lingo-1参与海马神经轴突、髓鞘及突触结构和功能损伤病理过程基础上，进一步研究发现惊厥后不同时期小鼠海马AMIGO3和Lingo-1表达均有增高，且AMIGO3表达水平明显高于Lingo-1，采用重组腺病毒载体调控AMIGO3蛋白表达变化后，能够改善惊厥所致还是神经元髓鞘、轴突和突触损伤。同时进一步研究发现调控AMIGO3表达后主要通过调控调控下游ROCK/RhoA信号发挥作用，而调控AMIGO3表达后对EGFR/PI3K/AKT信号未发现明显影响。为进一步深入研究惊厥后癫痫形成和脑损伤机制提供新的方向。