Li Jie, Mi Xiujuan, Chen Ling, Jiang Guohui, Wang Na, Zhang Yujiao, Deng Wanni, Wang Zhihua, Chen Guojun, Wang Xuefeng
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 YouYi Road, Chongqing, 400016, China.
Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China.
Mol Neurobiol. 2016 May;53(4):2715-25. doi: 10.1007/s12035-015-9406-9. Epub 2015 Aug 30.
Epilepsy is one of the most common and severe neurologic diseases. The mechanisms of epilepsy are still not fully understood. Dock3 (dedicator of cytokinesis 3) is one of the new kinds of guanine-nucleotide exchange factors (GEF) and plays an important role in neuronal synaptic plasticity and cytoskeleton rearrangement; the same mechanisms were also found in epilepsy. However, little is known regarding the expression of Dock3 in the epileptic brain and whether Dock3 interventions affect the epileptic process. In this study, we showed that the expression of Dock3 significantly increased in IE patients and a lithium-pilocarpine epilepsy model compared with the controls. Inhibition of Dock3 by Dock3 shRNA impaired the severity of status epilepticus in the acute stage and decreased the spontaneous recurrent seizures times in the chronic stage of lithium-pilocarpine model and decreased the expression of rac1-GTP. Consistent with decreased expression of Dock3, the latent period in a pentylenetetrazole kindling model also increased. Our results demonstrated that the increased expression of Dock3 in the brain is associated with epileptogenesis and specific inhibition of Dock3 may be a potential target in preventing the development of epilepsy in patients.
癫痫是最常见且严重的神经系统疾病之一。癫痫的发病机制仍未完全明确。Dock3（胞质分裂 dedicator 3）是新型鸟嘌呤核苷酸交换因子（GEF）之一，在神经元突触可塑性和细胞骨架重排中发挥重要作用；癫痫中也发现了相同机制。然而，关于Dock3在癫痫脑内的表达以及Dock3干预是否影响癫痫进程，目前所知甚少。在本研究中，我们发现与对照组相比，Dock3在颞叶内侧癫痫（IE）患者和锂 - 匹罗卡品癫痫模型中的表达显著增加。通过Dock3短发夹RNA（shRNA）抑制Dock3可减轻锂 - 匹罗卡品模型急性期癫痫持续状态的严重程度，并减少慢性期的自发复发性癫痫发作次数，同时降低rac1 - GTP的表达。与Dock3表达降低一致，戊四氮点燃模型中的潜伏期也延长。我们的结果表明，脑内Dock3表达增加与癫痫发生相关，特异性抑制Dock3可能是预防患者癫痫发展的潜在靶点。
