Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08823, Korea.
Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea.
J Neurosci. 2024 Oct 9;44(41):e1810232024. doi: 10.1523/JNEUROSCI.1810-23.2024.
Targeting altered expression and/or activity of GABA (γ-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 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.
靶向改变 GABA（γ-氨基丁酸）转运体（GATs）的表达和/或活性可为与年龄相关的损伤提供治疗益处，包括认知功能障碍。然而，GATs 的转录调控机制尚不清楚。在本研究中，我们证明了干扰素基因刺激物（STING）可在上调大脑中 GAT1 和 GAT3 的表达，从而导致认知功能障碍。STING 的遗传和药理学干预抑制了 GAT1 和 GAT3 的表达，增加了周围 GABA 浓度，从而增强了海马主神经元的紧张性 GABA 抑制，导致小鼠的空间学习和工作记忆缺陷，而不依赖于 I 型干扰素。刺激 STING→GAT 途径可有效地恢复 STING 缺陷型小鼠模型的认知功能障碍。我们的研究首次揭示了 STING 信号通路以细胞自主的方式调节 GAT 的表达，因此可能成为 GABA 能认知缺陷的新靶点。
