Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea.
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
Cell Rep. 2020 Feb 11;30(6):1995-2005.e5. doi: 10.1016/j.celrep.2020.01.053.
Gephyrin interacts with various GABAergic synaptic proteins to organize GABAergic synapse development. Among the multitude of gephyrin-binding proteins is IQSEC3, a recently identified component at GABAergic synapses that acts through its ADP ribosylation factor-guanine nucleotide exchange factor (ARF-GEF) activity to orchestrate GABAergic synapse formation. Here, we show that IQSEC3 knockdown (KD) reduced GABAergic synaptic density in vivo, suggesting that IQSEC3 is required for GABAergic synapse maintenance in vivo. We further show that IQSEC3 KD in the dentate gyrus (DG) increases seizure susceptibility and triggers selective depletion of somatostatin (SST) peptides in the DG hilus in an ARF-GEP activity-dependent manner. Strikingly, selective introduction of SST into SST interneurons in DG-specific IQSEC3-KD mice reverses GABAergic synaptic deficits. Thus, our data suggest that IQSEC3 is required for linking gephyrin-GABA receptor complexes with ARF-dependent pathways to prevent aberrant, runaway excitation and thereby contributes to the integrity of SST interneurons and proper GABAergic synapse maintenance.
Gephyrin 与各种 GABA 能突触蛋白相互作用，以组织 GABA 能突触的发育。在众多与 gephyrin 结合的蛋白中，IQSEC3 是 GABA 能突触的一个新鉴定的组成部分，它通过其 ADP 核糖基化因子-鸟嘌呤核苷酸交换因子（ARF-GEF）活性来协调 GABA 能突触的形成。在这里，我们表明 IQSEC3 敲低（KD）减少了体内 GABA 能突触的密度，这表明 IQSEC3 对于体内 GABA 能突触的维持是必需的。我们进一步表明，在齿状回（DG）中 IQSEC3 KD 增加了癫痫易感性，并以 ARF-GEP 活性依赖性方式触发了 DG 门区中生长抑素（SST）肽的选择性耗竭。引人注目的是，将 SST 选择性引入 DG 特异性 IQSEC3-KD 小鼠中的 SST 中间神经元中可逆转 GABA 能突触缺陷。因此，我们的数据表明，IQSEC3 对于将 gephyrin-GABA 受体复合物与 ARF 依赖性途径联系起来以防止异常的、失控的兴奋是必需的，从而有助于 SST 中间神经元的完整性和适当的 GABA 能突触的维持。
