Robo1 在戊四唑诱发癫痫小鼠模型中的作用机制

Ibrain Pub Date : 2023-08-15 DOI:10.1002/ibra.12127
Zheng Liu, Wei Huang, Man-Min Zhu, Zhong-Xiang Xu, Zu-Cai Xu, Chang-Yin Yu, Hao Huang
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摘要

神经网络假说是耐药性癫痫的重要发病机制之一。轴突通过突触重塑和脑组织重塑引导分子,可能导致异常神经网络的形成。因此,轴突导向在疾病进展中起着至关重要的作用。然而,尽管Robo1是轴突导向的重要组成部分之一,但Robo1在癫痫中的作用仍不清楚。本研究旨在探索 Robo1 在癫痫中的作用机制。雄性成年 C57BL/6 小鼠腹腔注射戊四唑,建立癫痫模型。在注射戊四唑前两周,小鼠颅内注射慢病毒(LV)。利用Western印迹、免疫荧光染色、高尔基体染色和视频监控分析了对照组、LV介导的Robo1短发夹RNA组、空载体对照LV组和正常生理盐水组之间Robo1的不同表达。在戊四唑诱导的癫痫小鼠模型中,Robo1在海马中增加;慢病毒敲除Robo1延长了小鼠癫痫发作的潜伏期,降低了癫痫发作等级,并导致树突棘密度下降,而成熟树突棘的数量保持不变。我们推测,Robo1 通过对树突棘形态和密度的影响,与癫痫的发生和发展有关。在 Robo1 基因敲除病毒干预下,癫痫小鼠的发作等级更低,潜伏期更长。后续研究结果表明,Robo1 可能通过影响树突棘密度和形态来调节癫痫发作。Robo1的下调可能通过降低树突棘的密度和维持更多的成熟树突棘来负向调节癫痫的发生。
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Mechanism of Robo1 in the pentylenetetrazol-kindled epilepsy mouse model

The neural network hypothesis is one of the important pathogenesis of drug-resistant epilepsy. Axons guide molecules through synaptic remodeling and brain tissue remodeling, which may result in the formation of abnormal neural networks. Therefore, axon guidance plays a crucial role in disease progression. However, although Robo1 is one of the important components of axon guidance, the role of Robo1 in epilepsy remains unclear. In this study, we aimed to explore the mechanism of Robo1 in epilepsy. Male adult C57BL/6 mice were intraperitoneally injected with pentylenetetrazol to establish an epilepsy model. Lentivirus (LV) was given via intracranial injection 2 weeks before pentylenetetrazol injection. Different expressions of Robo1 between the control group, LV-mediated Robo1 short hairpin RNA group, empty vector control LV group, and normal saline group were analyzed using Western blot, immunofluorescence staining, Golgi staining, and video monitoring. Robo1 was increased in the hippocampus in the pentylenetetrazol-induced epilepsy mouse model; lentiviral Robo1 knockdown prolonged the latency of seizure and reduced the seizure grade in mice and resulted in a decrease in dendritic spine density, while the number of mature dendritic spines was maintained. We speculate that Robo1 has been implicated in the development and progression of epilepsy through its effects on dendritic spine morphology and density. Epileptic mice with Robo1 knockdown virus intervention had lower seizure grade and longer latency. Follow-up findings suggest that Robo1 may modulate seizures by affecting dendritic spine density and morphology. Downregulation of Robo1 may negatively regulate epileptogenesis by decreasing the density of dendritic spines and maintaining a greater number of mature dendritic spines.

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