Abstract：
Epilepsy is a common neurological disorder which can cause significant morbidity and mortality. N6-methyladenosine (m6A), the most common chemical epigenetic modification among mRNA post-transcriptional modifications, implicated in various physiological and pathological processes, but its role in epilepsy is still unknown. Here, we provide strong evidences in support of an association of m6A and its regulatory proteins with epilepsy. Our results indicated that the level of m6A was declined significantly in the dentate gyrus (DG) of hippocampus of pentylenetetrazol (PTZ)-induced seizure mice. Both the seizure-like behaviors and the excessive activation of DG area neuron were significantly mitigated after the administration of m6A agonist betaine. Mechanically, we found that both the m6A methyltransferase METTL14 and recognition protein YTHDC1 were decreased by PTZ stimulation, which might contribute to the reduced m6A level. Additionally, DG-specific over-expression of METTL14 or YTHDC1 by lentivirus injection could significantly ameliorate seizure-like behaviors and prevent the excessive activation of neuron in epilepsy mice induced by PTZ injection, which might be due to the normalized m6A level. Together, this study identified that METTL14/YTHDC1-mediated m6A modification could participate in seizure-like behaviors, which might provide m6A regulation as a potential and novel therapeutic strategy for epilepsy.
摘要：
癫痫是一种常见的神经系统疾病，可导致大量的发病率和死亡率。N6-甲基腺苷（m6A），mRNA转录后修饰中最常见的化学表观遗传修饰，涉及各种生理和病理过程，但其在癫痫中的作用尚不清楚。这里,我们提供了有力的证据支持m6A及其调节蛋白与癫痫的相关性.我们的结果表明，戊四氮（PTZ）诱发的癫痫小鼠海马齿状回（DG）中m6A的水平显着下降。给予m6A激动剂甜菜碱后，癫痫样行为和DG区神经元的过度激活均显着减轻。机械上,我们发现，m6A甲基转移酶METTL14和识别蛋白YTHDC1被PTZ刺激降低，这可能有助于降低m6A水平。此外,慢病毒注射DG特异性过表达METTL14或YTHDC1可显著改善PTZ注射诱导的癫痫小鼠癫痫样行为，防止神经元过度激活。这可能是由于归一化的m6A水平。一起,这项研究确定METTL14/YTHDC1介导的m6A修饰可以参与癫痫样行为，这可能提供m6A调节作为癫痫的潜在和新的治疗策略。
