Depolarized GABAergic Signaling in Subicular Microcircuits Mediates Generalized Seizure in Temporal Lobe Epilepsy
Depolarized GABAergic Signaling in Subicular Microcircuits Mediates Generalized Seizure in Temporal Lobe Epilepsy
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皮下微电路中的去极化 GABA 信号介导颞叶癫痫的全身性癫痫发作
DOI：
10.1016/j.neuron.2017.06.004
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发表时间：
2017-07-05
期刊：
影响因子：
16.2
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Wang, Yi;Xu, Cenglin;Chen, Zhong
继发性全身性癫痫发作（sGS）是颞叶癫痫（TLE）残疾的主要根源，其细胞/回路机制尚不清楚。在这里，我们发现，与没有 sGS 的患者相比，患有 sGS 的临床 TLE 患者的下托体积明显减少。此外，在小鼠模型中使用光遗传学和细胞外电生理记录，我们发现皮下 GABA 能神经元的光激活通过抑制锥体神经元的放电来延迟 sGS 的获得。一旦稳定获得 sGS，GABA 能神经元的光激活就会通过去极化 GABA 能信号传导加剧 sGS 表达。皮下小清蛋白，但不是生长抑素亚型 GABA 能神经元，在 sGS 表达中很容易去极化。最后，用质子泵 Arch（而不是氯泵 NpHR3.0）对皮下锥体神经元进行基因靶向光刺激，减轻了 sGS 表达。这些结果表明，皮下微电路中的去极化 GABA 信号传导介导 TLE 中的 sGS。这对于理解 sGS 背后的病理神经元回路可能具有治疗意义。
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.