Department of Medical Science, College of Medicine and Brain Research Institute, Chungnam National University, Daejeon, Republic of Korea.
Department of Physiology, College of Medicine and Brain Research Institute, Chungnam National University, Daejeon, Republic of Korea.
Glia. 2020 May;68(5):1065-1080. doi: 10.1002/glia.23762. Epub 2019 Dec 13.
Tonic extrasynaptic GABA receptor (GABA R) activation is under the tight control of tonic GABA release from astrocytes to maintain the brain's excitation/inhibition (E/I) balance; any slight E/I balance disturbance can cause serious pathological conditions including epileptic seizures. However, the pathophysiological role of tonic GABA release from astrocytes has not been tested in epileptic seizures. Here, we report that pharmacological or genetic intervention of the GABA-permeable Bestrophin-1 (Best1) channel prevented the generation of tonic GABA inhibition, disinhibiting CA1 pyramidal neuronal firing and augmenting seizure susceptibility in kainic acid (KA)-induced epileptic mice. Astrocyte-specific Best1 over-expression in KA-injected Best1 knockout mice fully restored the generation of tonic GABA inhibition and effectively suppressed seizure susceptibility. We demonstrate for the first time that tonic GABA from reactive astrocytes strongly contributes to the compensatory shift of E/I balance in epileptic hippocampi, serving as a good therapeutic target against altered E/I balance in epileptic seizures.
紧张型 extrasynaptic GABA 受体 (GABA R) 的激活受到来自星形胶质细胞的紧张型 GABA 释放的严格控制，以维持大脑的兴奋/抑制 (E/I) 平衡；任何轻微的 E/I 平衡紊乱都可能导致严重的病理状况，包括癫痫发作。然而，星形胶质细胞紧张型 GABA 释放的病理生理作用尚未在癫痫发作中得到测试。在这里，我们报告说，药物或遗传干预 GABA 通透性 Bestrophin-1 (Best1) 通道可防止紧张型 GABA 抑制的产生，从而解除 CA1 锥体神经元的抑制并增加海人酸 (KA) 诱导的癫痫小鼠的癫痫易感性。在 KA 注射的 Best1 敲除小鼠中，星形胶质细胞特异性过表达 Best1 可完全恢复紧张型 GABA 抑制的产生，并有效抑制癫痫易感性。我们首次证明，反应性星形胶质细胞中的紧张型 GABA 强烈促成癫痫海马中 E/I 平衡的代偿性转变，是治疗癫痫发作中 E/I 平衡改变的良好治疗靶点。
