Tonic extrasynaptic GABAA receptor (GABAA 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.

中文翻译：

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从反应性星形胶质细胞释放Bestrophin1介导的滋补GABA可以阻止海藻酸盐注射海马体中癫痫发作易发性网络的发展。

滋补突触外GABAA受体（GABAA R）的激活受星形胶质细胞释放的滋补GABA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平衡紊乱都会导致严重的病理状况，包括癫痫发作。然而，尚未在癫痫性癫痫发作中检测出星形胶质细胞释放滋补GABA的病理生理作用。在这里，我们报告的药理或遗传干预的GABA渗透性Bestrophin-1（Best1）通道阻止了强直GABA的抑制作用的产生，抑制了CA1锥体神经元的放电并增强了海藻酸（KA）诱发的癫痫小鼠的癫痫发作易感性。在注射KA的Best1基因敲除小鼠中，星形胶质细胞特异性的Best1过表达完全恢复了滋补GABA抑制作用的产生，并有效地抑制了癫痫发作的易感性。我们首次证明，来自反应性星形胶质细胞的滋补GABA强烈促进癫痫海马中E / I平衡的代偿性转变，作为对抗癫痫发作中E / I平衡改变的良好治疗靶标。