The role of voltage-gated chloride channels in the epileptogenesis of temporal lobe epilepsy
Kai-Feng Shen,
Xiao-Lin Yang,
Guo-Long Liu,
Gang Zhu,
Zhong-Ke Wang,
Xian-Jun Shi,
Ting-Ting Wang,
Zhi-Feng Wu,
Sheng-Qing Lv,
Shi-Yong Liu,
Hui Yang,
Chun-Qing Zhang
Affiliations
Kai-Feng Shen
Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China
Xiao-Lin Yang
Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China
Guo-Long Liu
Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China
Gang Zhu
Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China
Zhong-Ke Wang
Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China
Xian-Jun Shi
Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China
Ting-Ting Wang
Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China
Zhi-Feng Wu
Department of Pediatrics, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China
Sheng-Qing Lv
Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China
Shi-Yong Liu
Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China
Hui Yang
Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China
Chun-Qing Zhang
Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China; Correspondence: Chun-Qing Zhang, MD, PhD. Department of Neurosurgery, Xinqiao Hospital, Army Medical University, 2-V Xinqiao Street, Chongqing 400037, China. Phone: +86-23-68774010, Fax: +86-23-65218204.
Background: Temporal lobe epilepsy (TLE) is the most common intractable epilepsy in adults, and elucidation of the underlying pathological mechanisms is needed. Voltage-gated chloride channels (ClC) play diverse physiological roles in neurons. However, less is known regarding their functions in the epilepogenesis of TLE. Methods: ClC-mediated current and the spontaneous inhibitory synaptic currents (sIPSC) in hippocampal neurons of epileptic lesions were investigated by electrophysiological recording. The EEG data were analyzed by Z-scored wavelet and Fourier transformations. The expression of ClC-3, a member of ClC gene family, was detected by immunostaining and western blot. Findings: ClC-mediated current was increased in the hippocampal neurons of chronic TLE mice. Application of chloride channel blockers, NPPB (5-Nitro-2- [3-phenylpropylamino] benzoic acid) and DIDS (4,4’-Diisothiocyanato-2,2’-stilbenedisulfonic acid disodium salt) reduced ClC-mediated current and increased inhibitory synaptic transmission in TLE mice. NPPB and DIDS reduced the seizure frequency and the average absolute power of ictal high-frequency oscillations (HFOs, 80-500 Hz) in TLE mice. In addition, both drugs induced outwardly rectified currents, which might be tonic inhibitory currents in the hippocampal neurons of TLE patients. Furthermore, the expression of ClC-3 was increased in the hippocampus of TLE mice and patients and positively correlated with both the absolute power and number of ictal HFOs per seizure in the sclerotic hippocampus. Interpretation: These data suggest that ClC participate in the epilepogenetic process of TLE and the inhibition of ClC may have anti-epileptic effect. Funding: This work was supported by National Natural Science Foundation of China (No. 81601143, No. 81771217).
