Targeting altered expression and/or activity of GABA (-aminobutyric acid) transporters (GATs) provide therapeutic benefit for age-related impairments, including cognitive dysfunction. However, the mechanisms underlying the transcriptional regulation of GATs are unknown. In the present study, we demonstrated that the stimulator of interferon genes (STING) upregulates GAT1 and GAT3 expression in the brain, which resulted in cognitive dysfunction. Genetic and pharmacological intervention of STING suppressed the expression of both GAT1 and GAT3, increased the ambient GABA concentration, and therefore, enhanced tonic GABA_A inhibition of principal hippocampal neurons, resulting in spatial learning and working memory deficits in mice in a type I interferon-independent manner. Stimulation of the STING->GAT pathway efficiently restored cognitive dysfunction in STING-deficient mice models. Our study uncovered for the first time that the STING signaling pathway regulates GAT expression in a cell autonomous manner and therefore could be a novel target for GABAergic cognitive deficits.

靶向 GABA （-氨基丁酸） 转运蛋白 （GAT） 的表达和/或活性的改变为年龄相关障碍（包括认知功能障碍）提供治疗益处。然而，GAT 转录调控的潜在机制尚不清楚。在本研究中，我们证明了干扰素基因刺激物 （STING） 上调大脑中 GAT1 和 GAT3 的表达，从而导致认知功能障碍。STING 的遗传和药物干预抑制了 GAT1 和 GAT3 的表达，增加了环境 GABA 浓度，因此增强了对主要海马神经元的强直性 GABA_A 抑制，导致小鼠空间学习和工作记忆缺陷以 I 型干扰素非依赖性方式。刺激 STING->GAT 通路可有效恢复 STING 缺陷小鼠模型的认知功能障碍。我们的研究首次发现 STING 信号通路以细胞自主方式调节 GAT 表达，因此可能是 GABA 能认知缺陷的新靶点。