Neuron：浙江大學陳忠教授課題組解析顳葉癲癇繼發性全身性大發作的發病機制

2017年6月22日，國際著名學術雜誌《Cell》子刊《Neuron》雜誌線上發表了浙江大學藥學院陳忠教授課題組題為《Depolarized GABAergic Signaling in Subicular Microcircuits Mediates Generalized Seizure in Temporal Lobe Epilepsy》的文章。研究發現顳葉癲癇繼發性全身性大發作與下托腦區特異性地存在異常去極化信號通路相關，

揭示了下托區GABA神經微環路在癲癇發病中作用機制，研究結果為精准治療顳葉癲癇的藥物新靶點研究提供了非常重要的實驗依據。課題組博士後汪儀和徐層林等人為論文第一作者，陳忠教授為論文通訊作者。

癲癇是一種常見的中樞神經系統疾病，以腦內同步化放電引起的反復且突發性的發作為特徵。經典學說認為癲癇發作是由於腦內興奮--抑制失衡理論引起，

因此臨床上常用增強腦內抑制性功能的藥物治療癲癇，但是不僅副作用大，而且30%將產生耐藥。陳忠教授課題組前期研究在《EBioMedicine》雜誌的報導了啟動內嗅皮層中的興奮性谷氨酸能神經元反而產生抑制癲癇的作用，首次提示了精准靶向特定神經元的重要性(該論文2017年初發表就立即被F1000推薦)。本研究在前期工作的基礎上，進一步聚焦解析了顳葉癲癇繼發性全身性大發作的發病機制。

研究中，陳忠教授課題組的研究人員首先利用附屬二院癲癇中心臨床顳葉患者結構磁共振圖像，發現存在全身性大發作的顳葉癲癇患者的下托區結構萎縮異常嚴重。進一步，在不同的小鼠顳葉模型中，研究人員利用光遺傳學選擇性啟動下托區一類抑制性的GABA能神經元，發現其可以抑制另外一類錐體神經元的放電，並且抑制繼發性癲癇大發作的形成。

有意思的是，一旦大發作穩定獲得後，再啟動這類抑制性的GABA能神經元卻能增強一部分錐體神經元的放電，進而加重癲癇大發作，提示GABA能神經元在癲癇大發作的形成和發作階段存在完全不同的作用。下托GABA能神經元在大發作的這種功能轉變是由氯轉運蛋白NKCC1和KCC2表達改變引起的異常去極化的GABA能信號所介導的，用藥理學手段或者基因干預手段抑制NKCC1的功能，可以逆轉啟動GABA能神經元的促癲癇作用。同時，這種去極化的GABA能神經元具有細胞亞型特異性，啟動下托小清蛋白陽性的GABA能神經元促進大發作，而啟動下托的生長抑素陽性的GABA能神經元抑制大發作，提示下托小清蛋白陽性的GABA能神經元比生長抑素陽性的GABA能神經元容易產生去極化。最後，研究人員直接用抑制性光敏感質子泵Arch(而非氯離子泵NpHR3.0)抑制下托的錐體細胞可以較好的抑制大發作，進一步證實了去極化現象的存在。該研究首次在體水準上闡明了由氯轉運蛋白引起的下托腦區內GABA神經微環路的異常去極化信號對於顳葉癲癇中的繼發性的全身性大發作具有重要作用。這一發現表明在癲癇的不用階段GABA能神經元具有完全不用的作用，且這種特性具有細胞亞型特異性，進一步補充了經典的癲癇發病機制學說，有望為臨床精准治療顳葉癲癇提供一種新的藥物靶點和治療策略。

原文連結：

原文摘要：

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.

原文連結：

原文摘要：

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.