Astrocytic Acid-Sensing Ion Channel 1a Contributes to the Development of Chronic Epileptogenesis.
Astrocytic Acid-Sensing Ion Channel 1a Contributes to the Development of Chronic Epileptogenesis.
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星形胶质细胞酸敏感离子通道 1a 有助于慢性癫痫发生的发展
DOI：
10.1038/srep31581
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发表时间：
2016-08-16
影响因子：
4.6
通讯作者：
Jiang W
中科院分区：
文献类型：
--
作者：
Yang F;Sun X;Ding Y;Ma H;Yang TO;Ma Y;Wei D;Li W;Xu T;Jiang W
揭示脑损伤后癫痫发生的机制是一个尚未解决的医学挑战。虽然组织病理学研究表明，反应性星形胶质增生和组织酸中毒是致痫灶的突出特征，但它们在癫痫发生中的作用尚不清楚。在这里，我们探讨星形胶质细胞酸感应离子通道1a （ASIC1a）是否有助于慢性癫痫的发展。在颞叶癫痫（TLE）患者和癫痫小鼠的海马反应性星形胶质细胞中检测到高水平的ASIC1a。细胞外酸中毒在培养的星形胶质细胞中引起显著的Ca2+内流，并且这种内流对asic1a特异性阻滞剂psalmotoxin 1 （PcTX1）的抑制敏感。此外，制备了携带GFAP启动子和ASIC1a shRNA或cDNA的重组腺相关病毒（rAAV）载体，分别抑制或恢复ASIC1a在星形胶质细胞中的表达。将rAAV-ASIC1a-shRNA注射到宽型TLE小鼠齿状回模型中，可抑制星形细胞ASIC1a表达，减少自发性癫痫发作。相比之下，rAAV-ASIC1a-cDNA在ASIC1a敲除TLE小鼠模型中恢复星形细胞ASIC1a表达，并增加自发癫痫发作的频率。综上所述，我们的研究结果表明星形细胞ASIC1a可能是治疗癫痫的一个有吸引力的新靶点。
Unraveling mechanisms underlying epileptogenesis after brain injury is an unmet medical challenge. Although histopathological studies have revealed that reactive astrogliosis and tissue acidosis are prominent features in epileptogenic foci, their roles in epileptogenesis remain unclear. Here, we explored whether astrocytic acid-sensing ion channel-1a (ASIC1a) contributes to the development of chronic epilepsy. High levels of ASIC1a were measured in reactive astrocytes in the hippocampi of patients with temporal lobe epilepsy (TLE) and epileptic mice. Extracellular acidosis caused a significant Ca2+influx in cultured astrocytes, and this influx was sensitive to inhibition by the ASIC1a-specific blocker psalmotoxin 1 (PcTX1). In addition, recombinant adeno-associated virus (rAAV) vectors carrying a GFAP promoter in conjunction with ASIC1a shRNA or cDNA were generated to suppress or restore, respectively, ASIC1a expression in astrocytes. Injection of rAAV-ASIC1a-shRNA into the dentate gyrus of the wide type TLE mouse model resulted in the inhibition of astrocytic ASIC1a expression and a reduction in spontaneous seizures. By contrast, rAAV-ASIC1a-cDNA restored astrocytic ASIC1a expression in an ASIC1a knock-out TLE mouse model and increased the frequency of spontaneous seizures. Taken together, our results reveal that astrocytic ASIC1a may be an attractive new target for the treatment of epilepsy.