Synapse and Neural Circuit Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Rep. 2021 Mar 23;34(12):108899. doi: 10.1016/j.celrep.2021.108899.
Tonic inhibition mediated by extrasynaptic γ-aminobutyric acid type A receptors (GABARs) critically regulates neuronal excitability and brain function. However, the mechanisms regulating tonic inhibition remain poorly understood. Here, we report that Shisa7 is critical for tonic inhibition regulation in hippocampal neurons. In juvenile Shisa7 knockout (KO) mice, α5-GABAR-mediated tonic currents are significantly reduced. Mechanistically, Shisa7 is crucial for α5-GABAR exocytosis. Additionally, Shisa7 regulation of tonic inhibition requires protein kinase A (PKA) that phosphorylates Shisa7 serine 405 (S405). Importantly, tonic inhibition undergoes activity-dependent regulation, and Shisa7 is required for homeostatic potentiation of tonic inhibition. Interestingly, in young adult Shisa7 KOs, basal tonic inhibition in hippocampal neurons is unaltered, largely due to the diminished α5-GABAR component of tonic inhibition. However, at this stage, tonic inhibition oscillates during the daily sleep/wake cycle, a process requiring Shisa7. Together, these data demonstrate that intricate signaling mechanisms regulate tonic inhibition at different developmental stages and reveal a molecular link between sleep and tonic inhibition.
由突触外 γ-氨基丁酸 A 型受体 (GABARs) 介导的紧张性抑制对神经元兴奋性和大脑功能的调节起着至关重要的作用。然而，调节紧张性抑制的机制仍知之甚少。在这里，我们报告 Shisa7 对海马神经元紧张性抑制的调节至关重要。在幼年 Shisa7 敲除 (KO) 小鼠中，α5-GABAR 介导的紧张性电流显著减少。从机制上讲，Shisa7 对于 α5-GABAR 的胞吐作用至关重要。此外，Shisa7 对紧张性抑制的调节需要蛋白激酶 A (PKA)，PKA 可以磷酸化 Shisa7 的丝氨酸 405 (S405)。重要的是，紧张性抑制会发生活动依赖性调节，而 Shisa7 是紧张性抑制的同源性增强所必需的。有趣的是，在年轻成年的 Shisa7 KO 中，海马神经元的基础紧张性抑制没有改变，这主要是由于紧张性抑制的α5-GABAR 成分减少。然而，在这个阶段，紧张性抑制在日常的睡眠/觉醒周期中会发生振荡，这一过程需要 Shisa7。总的来说，这些数据表明，复杂的信号机制在不同的发育阶段调节紧张性抑制，并揭示了睡眠和紧张性抑制之间的分子联系。
