Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
J Cell Mol Med. 2020 Sep;24(18):10573-10588. doi: 10.1111/jcmm.15677. Epub 2020 Aug 10.
Epileptogenesis is a potential process. Mossy fibre sprouting (MFS) and synaptic plasticity promote epileptogenesis. Overexpression of repulsive guidance molecule a (RGMa) prevents epileptogenesis by inhibiting MFS. However, other aspects underlying the RGMa regulatory process of epileptogenesis have not been elucidated. We studied whether RGMa could be modulated by microRNAs and regulated RhoA in epileptogenesis. Using microRNA databases, we selected four miRNAs as potential candidates. We further experimentally confirmed miR-20a-5p as a RGMa upstream regulator. Then, in vitro, by manipulating miR-20a-5p and RGMa, we investigated the regulatory relationship between miR-20a-5p, RGMa and RhoA, and the effects of this pathway on neuronal morphology. Finally, in the epilepsy animal model, we determined whether the miR-20a-5p-RGMa-RhoA pathway influenced MFS and synaptic plasticity and then modified epileptogenesis. Our results showed that miR-20a-5p regulated RGMa and that RGMa regulated RhoA in vitro. Furthermore, in primary hippocampal neurons, the miR-20a-5p-RGMa-RhoA pathway regulated axonal growth and neuronal branching; in the PTZ-induced epilepsy model, silencing miR-20a-5p prevented epileptogenesis through RGMa-RhoA-mediated synaptic plasticity but did not change MFS. Overall, we concluded that silencing miR-20a-5p inhibits axonal growth and neuronal branching and prevents epileptogenesis through RGMa-RhoA-mediated synaptic plasticity in the PTZ-induced epilepsy model, thereby providing a possible strategy to prevent epileptogenesis.
癫痫发生是一个潜在的过程。苔藓纤维发芽（MFS）和突触可塑性促进癫痫发生。排斥性导向分子 a（RGMa）的过表达通过抑制 MFS 来预防癫痫发生。然而，RGMa 调节癫痫发生的其他方面尚未阐明。我们研究了 RGMa 是否可以被 microRNAs 调节以及在癫痫发生中调节 RhoA。使用 microRNA 数据库，我们选择了四个 microRNA 作为潜在的候选 microRNA。我们进一步通过实验证实了 miR-20a-5p 是 RGMa 的上游调节 microRNA。然后，在体外，通过操纵 miR-20a-5p 和 RGMa，我们研究了 miR-20a-5p、RGMa 和 RhoA 之间的调节关系，以及该途径对神经元形态的影响。最后，在癫痫动物模型中，我们确定了 miR-20a-5p-RGMa-RhoA 途径是否影响 MFS 和突触可塑性，从而改变癫痫发生。我们的结果表明，miR-20a-5p 调节 RGMa，而 RGMa 调节体外的 RhoA。此外，在原代海马神经元中，miR-20a-5p-RGMa-RhoA 途径调节轴突生长和神经元分支；在 PTZ 诱导的癫痫模型中，沉默 miR-20a-5p 通过 RGMa-RhoA 介导的突触可塑性来预防癫痫发生，但不改变 MFS。总的来说，我们得出结论，沉默 miR-20a-5p 通过 RGMa-RhoA 介导的突触可塑性抑制轴突生长和神经元分支，并在 PTZ 诱导的癫痫模型中预防癫痫发生，从而为预防癫痫发生提供了一种可能的策略。
