Zheng Yang-Min, Chen Bo, Jiang Jian-Dong, Zhang Jing-Pu
NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Front Mol Neurosci. 2018 Nov 26;11:378. doi: 10.3389/fnmol.2018.00378. eCollection 2018.
Epilepsy is a neuronal dysfunction syndrome characterized by transient and diffusely abnormal discharges of neurons in the brain. Previous studies have shown that mutations in the () gene cause a familial, fever-associated epilepsy syndrome. It is unclear as to whether the gene also correlates with other stimulations such as flashing and/or mediates the effects of antiepileptic drugs. In this study, we found that the expression of was present mainly in the brain and was negatively correlated with seizures in a pentylenetetrazole (PTZ)-induced seizure zebrafish model. The transcription of was inhibited by PTZ but rescued by valproate, a broad-spectrum epilepsy treatment drug. In the PTZ-seizure zebrafish model, knockdown aggravated larvae hyperexcitatory swimming and prompted abnormal trajectory movements, particularly under lighting stimulation; at the same time, the expression levels of the neuronal activity marker gene increased significantly in the brain. In contrast, overexpression attenuated seizures and decreased expression levels following PTZ-induced seizures in larvae. Thus, we speculated that a deficiency of gene expression may be related with the onset occurrence of clinical seizures, particularly photosensitive seizures. In addition, we found that berberine (BBR) reduced larvae hyperexcitatory locomotion and abnormal movement trajectory in a concentration-dependent manner, slowed down excessive photosensitive seizure-like swimming, and assisted in the recovery of the expression levels of STX1B. Under the downregulation of STX1B, BBR's roles were limited: specifically, it only slightly regulated the levels of the two genes and and the hyperexcitatory motion of zebrafish in dark conditions and had no effect on the overexcited swimming behavior seen in conjunction with lighting stimulation. These findings further demonstrate that STX1B protein levels are negatively correlated with a seizure and can decrease the sensitivity of the photosensitive response in a PTZ-induced seizure zebrafish larvae; furthermore, STX1B may partially mediate the anticonvulsant effect of BBR. Additional investigation regarding the relationship between STX1B, BBR, and seizures could provide new cues for the development of novel anticonvulsant drugs.
癫痫是一种神经元功能障碍综合征，其特征是大脑中神经元出现短暂且弥漫性的异常放电。先前的研究表明，（）基因的突变会导致一种与发热相关的家族性癫痫综合征。目前尚不清楚该基因是否也与其他刺激因素（如闪光）相关，以及是否介导抗癫痫药物的作用。在本研究中，我们发现该基因的表达主要存在于大脑中，并且在戊四氮（PTZ）诱导的癫痫斑马鱼模型中与癫痫发作呈负相关。该基因的转录受到PTZ的抑制，但可被广谱癫痫治疗药物丙戊酸挽救。在PTZ诱导癫痫的斑马鱼模型中，该基因敲低会加重幼虫的过度兴奋游泳行为，并促使轨迹运动异常，尤其是在光照刺激下；与此同时，大脑中神经元活动标记基因的表达水平显著增加。相反，该基因过表达可减轻癫痫发作，并降低幼虫经PTZ诱导癫痫发作后的表达水平。因此，我们推测该基因表达的缺乏可能与临床癫痫发作的发生有关，尤其是光敏性癫痫发作。此外，我们发现黄连素（BBR）以浓度依赖的方式减少幼虫的过度兴奋运动和异常运动轨迹，减缓过度的光敏性癫痫样游泳，并有助于恢复STX1B的表达水平。在STX1B下调的情况下，BBR的作用有限：具体而言，它仅轻微调节两个基因的水平以及斑马鱼在黑暗条件下的过度兴奋运动，并且对与光照刺激相关的过度兴奋游泳行为没有影响。这些发现进一步证明，STX1B蛋白水平与癫痫发作呈负相关，并且可以降低PTZ诱导癫痫的斑马鱼幼虫对光敏反应的敏感性；此外，STX1B可能部分介导了BBR的抗惊厥作用。关于STX1B、BBR和癫痫发作之间关系的进一步研究可能为新型抗惊厥药物的开发提供新线索。
