The Antagonism of 5-HT6 Receptor Attenuates Current-Induced Spikes and Improves Long-Term Potentiation via the Regulation of M-Currents in a Pilocarpine-Induced Epilepsy Model
The Antagonism of 5-HT6 Receptor Attenuates Current-Induced Spikes and Improves Long-Term Potentiation via the Regulation of M-Currents in a Pilocarpine-Induced Epilepsy Model
复制标题
5-HT6 受体的拮抗作用通过调节毛果芸香碱诱发的癫痫模型中的 M 电流来减弱电流诱发的尖峰并改善长时程增强
DOI：
10.3389/fphar.2020.00475
复制
发表时间：
2020
影响因子：
5.6
通讯作者：
Huang Huapin
中科院分区：
文献类型：
--
作者：
Zhu Chaofeng;Lin Rong;Liu Changyun;Huang Mingzhu;Lin Feng;Zhang Gan;Zhang Yuying;Miao Junjie;Lin Wanhui;Huang Huapin
最近的研究表明，减少M-电流促进癫痫发生和衰减突触重塑。神经突起的生长与中枢神经系统中5-HT 6受体（5-HT 6 R）的水平密切相关。然而，关于5-HT 6 R与M-电流的关系以及5-HT 6 R在M-电流调节中的作用的研究很少。在此，我们发现，5-HT 6 R的表达显着增加，KNCQ 2/3，M通道的主要成分，表达下降，在匹罗卡品诱导的慢性癫痫海马中，以时间依赖性的方式。有趣的是，SB 271046对5-HT 6 R的拮抗作用上调了KCNQ 2的表达，但不上调KCNQ 3的表达。SB 271046能显著改善慢性癫痫大鼠海马兴奋/抑制性失衡，改善LTP受损。进一步的机制探索发现SB 271046的上述作用可以被M通道抑制剂XE 991逆转，这也证实SB 271046确实可以改善异常M电流。提示5-HT 6 R拮抗剂可能通过上调M通道KCNQ 2的表达，降低慢性癫痫大鼠海马锥体神经元的兴奋性，改善受损的长时程增强。
Recent studies have documented that reduced M-current promotes epileptogenesis and attenuates synaptic remodeling. Neurite growth is closely related to the level of 5-HT6 receptor (5-HT6R) in the central nervous system. However, little research is available regarding the relation between 5-HT6R and M-current and the role of 5-HT6R in M-current regulation. Herein, we found that the expression of 5-HT6R was notably increased and the expression of KNCQ2/3, the main components of the M channel, was decreased in a time-dependent manner in pilocarpine-induced chronic epileptic hippocampus. Interestingly, antagonism of 5-HT6R by SB271046 upregulated the expression of KCNQ2 but not KCNQ3. SB271046 greatly alleviated excitatory/inhibitory imbalance and improved the impaired LTP in the chronic epileptic hippocampus. Further mechanism exploration revealed that the above effects of SB271046 can be reversed by the M-channel inhibitor XE991, which also confirmed that SB271046 can indeed improve abnormal M current. These data indicate that the antagonism of 5-HT6R may decrease the excitability of hippocampal pyramidal neurons in chronic epileptic rats and improve the impaired long-term potentiation by upregulating the expression of KCNQ2 in the M-channel.