Clock genes not only regulate the circadian rhythm of physiological activities but also participate in the pathogenesis of many diseases. Previous studies have documented the abnormal expression of clock genes in epilepsy. However, the molecular mechanism of brain and muscle Arnt-like protein 1 (Bmal1), one of the core clock genes, in the epileptogenesis and seizures of temporal lobe epilepsy (TLE) remain unclear. We first investigated the levels of Bmal1 and other clock proteins in the hippocampus of subjects with epilepsy to define the function of Bmal1. The levels of Bmal1 were decreased during the latent and chronic phases in the experimental group compared with those in the control group. Knockout of Bmal1 in hippocampal dentate gyrus (DG) neurons of Bmal1flox/flox mice by Synapsin 1 (Syn1) promoter AAV (adeno-associated virus) lowered the threshold of seizures induced by pilocarpine administration. High-throughput sequencing analysis showed that PCDH19 (protocadherin 19), a gene associated with epilepsy, was regulated by Bmal1. PCDH19 expression was also decreased in the hippocampus of epileptic mice. Furthermore, the higher levels of Bmal1 and PCDH19 were detected in patients with no hippocampal sclerosis (no HS) than in patients with HS International League Against Epilepsy (ILAE) type I and III. Altogether, these data suggest that decreased expression of clock gene Bmal1 may participate in epileptogenesis and seizures via PCDH19 in TLE.

中文翻译：

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时钟基因Bmal1表达降低参与颞叶癫痫的发病机制


时钟基因不仅调节生理活动的昼夜节律，还参与许多疾病的发病机制。先前的研究已经记录了癫痫中时钟基因的异常表达。然而，核心时钟基因之一的脑和肌肉Arnt样蛋白1（Bmal1）在颞叶癫痫（TLE）癫痫发生和发作中的分子机制仍不清楚。我们首先研究了癫痫患者海马中 Bmal1 和其他时钟蛋白的水平，以确定 Bmal1 的功能。与对照组相比，实验组潜伏期和慢性期Bmal1水平降低。通过突触蛋白 1 (Syn1) 启动子 AAV（腺相关病毒）敲除 Bmal1flox/flox 小鼠海马齿状回 (DG) 神经元中的 Bmal1，可降低毛果芸香碱诱导的癫痫发作阈值。高通量测序分析表明，与癫痫相关的基因PCDH19（原钙粘蛋白19）受Bmal1调控。癫痫小鼠海马中 PCDH19 的表达也有所下降。此外，在无海马硬化（无 HS）的患者中检测到的 Bmal1 和 PCDH19 水平高于国际抗癫痫联盟 (ILAE) I 型和 III 型 HS 患者。总之，这些数据表明时钟基因 Bmal1 表达的降低可能通过 TLE 中的 PCDH19 参与癫痫发生和癫痫发作。