INTRODUCTION Epileptogenesis is understood as the plastic process that produces a persistent reorganization of the brain's neural network after a precipitating injury (recurrent neonatal seizures, for instance) with a latent period, finally leading to neuronal hyperexcitability. Plasticity-related genes (PRGs), also known as lipid phosphate phosphatase-related proteins (PLPPRs), are regulators of mitochondrial membrane integrity and energy metabolism. This study was undertaken to determine whether PRG5 gene knockout contributes to the delayed hypersensitivity induced by developmental seizures and the aberrant sprouting of hippocampal mossy fibers, and to determine whether it is achieved through the mitochondrial pathway. Here, we developed a "twist" seizure model by coupling pilocarpine-induced juvenile seizures with later exposure to penicillin to test the long-term effects of PRG5 knockout on seizure latency through comparison with wild-type (WT) mice. Hippocampal mossy fiber sprouting (MFS) was detected by Timm staining. In order to clarify the mechanism of the adverse reactions triggered by PRG5 knockout, hippocampal HT22 neuronal cultures were exposed to glutamate, with or without PRG5 interference. Mitochondrial function, oxidative stress indicators and zinc ion content were detected. RESULTS PRG5 gene knockout significantly reduced the seizure latency, and aggravated the lowered seizure threshold induced by developmental seizures. Besides, knockout of the PRG5 gene reduced the MFS scores to a certain extent. Furthermore, PRG5 gene silencing significantly increases the zinc ion content in hippocampal neurons, impairs neuronal activity and mitochondrial function, and exacerbates glutamate-induced oxidative stress damage. CONCLUSION In summary, PRG5 KO is associated with significantly greater hypersusceptibility to juvenile seizures in PRG5(-/-) mice compared with WT mice. These effects may be related to the hippocampal zinc signaling. The effects do not appear to be related to changes in MFS because KO mice with juvenile seizures had the shortest seizure latencies but exhibited less MFS than WT mice with juvenile seizures.

中文翻译：

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PRG5 敲除通过加剧海马锌信号介导的线粒体损伤，导致对毛果芸香碱诱导的青少年癫痫发作的迟发性超易感性。

引言 癫痫发生被理解为在具有潜伏期的诱发性损伤（例如复发性新生儿癫痫发作）后产生大脑神经网络持续重组的塑性过程，最终导致神经元过度兴奋。可塑性相关基因 (PRGs)，也称为脂质磷酸酶相关蛋白 (PLPPRs)，是线粒体膜完整性和能量代谢的调节因子。本研究旨在确定 PRG5 基因敲除是否有助于由发育性癫痫发作和海马苔藓纤维的异常发芽引起的迟发性超敏反应，并确定它是否通过线粒体途径实现。在这里，我们开发了一个“扭曲” 通过将毛果芸香碱诱导的幼年癫痫发作与后来的青霉素暴露相结合的癫痫发作模型，通过与野生型 (WT) 小鼠的比较来测试 PRG5 敲除对癫痫发作潜伏期的长期影响。通过 Timm 染色检测海马苔藓纤维发芽 (MFS)。为了阐明 PRG5 敲除引发的不良反应的机制，海马 HT22 神经元培养物暴露于谷氨酸，有或没有 PRG5 干扰。检测线粒体功能、氧化应激指标和锌离子含量。结果 PRG5基因敲除显着降低了癫痫发作潜伏期，加重了发育性癫痫诱发的癫痫发作阈值降低。此外，PRG5基因的敲除在一定程度上降低了MFS分数。此外，PRG5基因沉默显着增加海马神经元中的锌离子含量，损害神经元活动和线粒体功能，并加剧谷氨酸诱导的氧化应激损伤。结论 总之，与 WT 小鼠相比，PRG5 KO 与 PRG5(-/-) 小鼠对幼年惊厥的高易感性显着相关。这些影响可能与海马锌信号传导有关。这种影响似乎与 MFS 的变化无关，因为 KO 幼年癫痫发作的小鼠的癫痫发作潜伏期最短，但 MFS 比幼年癫痫发作的 WT 小鼠少。与 WT 小鼠相比，PRG5 KO 与 PRG5(-/-) 小鼠对青少年癫痫发作的明显更大的超敏性相关。这些影响可能与海马锌信号传导有关。这种影响似乎与 MFS 的变化无关，因为 KO 幼年癫痫发作的小鼠的癫痫发作潜伏期最短，但 MFS 比幼年癫痫发作的 WT 小鼠少。与 WT 小鼠相比，PRG5 KO 与 PRG5(-/-) 小鼠对青少年癫痫发作的明显更大的超敏性相关。这些影响可能与海马锌信号传导有关。这种影响似乎与 MFS 的变化无关，因为 KO 幼年癫痫发作的小鼠的癫痫发作潜伏期最短，但 MFS 比幼年癫痫发作的 WT 小鼠少。