Institute of Pharmacology & Toxicology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Institute of Pharmacology & Toxicology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China; Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Brain Res. 2018 Dec 15;1701:126-136. doi: 10.1016/j.brainres.2018.09.008. Epub 2018 Sep 7.
GABAergic synaptic inhibition, which is a critical regulator of neuronal excitability, is closely involved in epilepsy. Interestingly, fast GABAergic transmission mediated by Cl permeable GABA receptors can bi-directionally exert both seizure-suppressing and seizure-promoting actions. Accumulating evidence suggests that chloride plasticity, the driving force of GABA receptor-mediated synaptic transmission, contributes to the double-edged role of GABAergic synapses in seizures. Large amounts of Cl influx can overwhelm Cl extrusion during seizures not only in healthy tissue in a short-term "activity-dependent" manner, but also in chronic epilepsy in a long-term, irreversible "pathology-dependent" manner related to the dysfunction of two chloride transporters: the chloride importer NKCC1 and the chloride exporter KCC2. In this review, we address the importance of chloride plasticity for the "activity-dependent" and "pathology-dependent" mechanisms underlying epileptic events and provide possible directions for further research, which may be clinically important for the design of GABAergic synapse-targeted precise therapeutic interventions for epilepsy.
GABA 能突触抑制是神经元兴奋性的重要调节因子，与癫痫密切相关。有趣的是，由 Cl 通透性 GABA 受体介导的快速 GABA 能传递可以双向发挥抑制和促进癫痫发作的作用。越来越多的证据表明，氯离子可塑性（GABA 受体介导的突触传递的驱动力）有助于 GABA 能突触在癫痫发作中发挥双刃剑作用。在癫痫发作期间，大量的 Cl 内流不仅可以在短时间内以“活动依赖性”方式压倒 Cl 外排，而且还可以在与两种氯离子转运体功能障碍相关的长期、不可逆的“与病理学相关”方式中压倒 Cl 外排：氯离子内流载体 NKCC1 和氯离子外流载体 KCC2。在这篇综述中，我们讨论了氯离子可塑性对于癫痫事件的“活动依赖性”和“病理学依赖性”机制的重要性，并为进一步的研究提供了可能的方向，这对于设计针对 GABA 能突触的精确治疗干预措施治疗癫痫可能具有重要的临床意义。
