Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea.
Core Protein Resources Center, DGIST, Daegu, South Korea.
Glia. 2020 Dec;68(12):2661-2673. doi: 10.1002/glia.23876. Epub 2020 Jul 9.
IQSEC3, a guanine nucleotide exchange factor for ADP-ribosylation factors (ARF-GEFs) is specifically expressed at GABAergic synapses, and its loss increases seizure susceptibility in mice. However, the contribution of microglia to initiation and/or progression of seizures in IQSEC3-deficient mice has not been investigated. In the current study, we show that mice with hippocampal dentate gyrus (DG)-specific IQSEC3 knockdown (KD) exhibit microglial activation and death of DG granule cell. Furthermore, treatment of IQSEC3-KD mice with minocycline, an inhibitor of microglial activation, blocks DG granule neuron cell death and the occurrence of spontaneous seizures without affecting GABAergic synapse deficits or loss of somatostatin. Our results suggest that microglial activation is involved in a subset of IQSEC3-KD-induced epileptogenesis stages, and that its regulation could be an alternative strategy for managing epilepsy.
IQSEC3 是一种鸟嘌呤核苷酸交换因子（ARF-GEFs），专门在 GABA 能突触中表达，其缺失会增加小鼠的癫痫易感性。然而，在 IQSEC3 缺陷小鼠中，小胶质细胞对癫痫发作的起始和/或进展的贡献尚未得到研究。在本研究中，我们发现海马齿状回（DG）特异性 IQSEC3 敲低（KD）的小鼠表现出小胶质细胞激活和 DG 颗粒细胞死亡。此外，用米诺环素（一种小胶质细胞激活抑制剂）治疗 IQSEC3-KD 小鼠可阻止 DG 颗粒神经元细胞死亡和自发性癫痫发作的发生，而不影响 GABA 能突触缺陷或生长抑素的丢失。我们的结果表明，小胶质细胞的激活参与了 IQSEC3-KD 诱导的癫痫发生阶段的一部分，其调节可能是治疗癫痫的一种替代策略。
