Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou 310027, China; Epilepsy Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310027, China.
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou 310027, China; College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Neuron. 2017 Jul 5;95(1):92-105.e5. doi: 10.1016/j.neuron.2017.06.004. Epub 2017 Jun 22.
Secondary generalized seizure (sGS) is a major source of disability in temporal lobe epilepsy (TLE) with unclear cellular/circuit mechanisms. Here we found that clinical TLE patients with sGS showed reduced volume specifically in the subiculum compared with those without sGS. Further, using optogenetics and extracellular electrophysiological recording in mouse models, we found that photoactivation of subicular GABAergic neurons retarded sGS acquisition by inhibiting the firing of pyramidal neurons. Once sGS had been stably acquired, photoactivation of GABAergic neurons aggravated sGS expression via depolarized GABAergic signaling. Subicular parvalbumin, but not somatostatin subtype GABAergic, neurons were easily depolarized in sGS expression. Finally, photostimulation of subicular pyramidal neurons genetically targeted with proton pump Arch, rather than chloride pump NpHR3.0, alleviated sGS expression. These results demonstrated that depolarized GABAergic signaling in subicular microcircuit mediates sGS in TLE. This may be of therapeutic interest in understanding the pathological neuronal circuitry underlying sGS. VIDEO ABSTRACT.
继发性全身性发作（sGS）是颞叶癫痫（TLE）致残的主要原因，其细胞/回路机制尚不清楚。在这里，我们发现伴有 sGS 的临床 TLE 患者与不伴有 sGS 的患者相比，其下托（subiculum）体积明显减小。此外，我们在小鼠模型中使用光遗传学和细胞外电生理记录发现，光激活下托 GABA 能神经元通过抑制锥体神经元的放电，延迟 sGS 的获得。一旦 sGS 被稳定获得，GABA 能神经元的光激活通过去极化 GABA 能信号加重 sGS 的表达。在 sGS 表达中，下托的 parvalbumin 而非 somatostatin 亚型 GABA 能神经元很容易去极化。最后，用光刺激质子泵 Arch 而非氯离子泵 NpHR3.0 基因靶向的下托锥体神经元，可减轻 sGS 的表达。这些结果表明，下托微电路中去极化的 GABA 能信号转导介导了 TLE 中的 sGS。这可能对理解 sGS 下的病理性神经元回路具有治疗意义。
