Institute of Pharmacology and Toxicology, University of Zürich, Zurich, 8057, Switzerland.
INSERM UMR-S, Paris, 75005, France.
eNeuro. 2018 Jan 18;5(1). doi: 10.1523/ENEURO.0203-17.2017. eCollection 2018 Jan-Feb.
Synaptic plasticity relies on the rapid changes in neurotransmitter receptor number at postsynaptic sites. Using superresolution photoactivatable localization microscopy imaging and quantum dot-based single-particle tracking in rat hippocampal cultured neurons, we investigated whether the phosphorylation status of the main scaffolding protein gephyrin influenced the organization of the gephyrin scaffold and GABA receptor (GABAR) membrane dynamics. We found that gephyrin phosphorylation regulates gephyrin microdomain compaction. Extracellular signal-regulated kinase 1/2 and glycogen synthase kinase 3β (GSK3β) signaling alter the gephyrin scaffold mesh differentially. Differences in scaffold organization similarly affected the diffusion of synaptic GABARs, suggesting reduced gephyrin receptor-binding properties. In the context of synaptic scaling, our results identify a novel role of the GSK3β signaling pathway in the activity-dependent regulation of extrasynaptic receptor surface trafficking and GSK3β, protein kinase A, and calcium/calmodulin-dependent protein kinase IIα pathways in facilitating adaptations of synaptic receptors.
突触可塑性依赖于突触后位点神经递质受体数量的快速变化。使用超分辨率光活化定位显微镜成像和基于量子点的单个粒子跟踪在大鼠海马培养神经元中，我们研究了主要支架蛋白神经胶质蛋白的磷酸化状态是否影响神经胶质蛋白支架和 GABA 受体 (GABAR) 膜动力学的组织。我们发现神经胶质蛋白磷酸化调节神经胶质蛋白微区的紧缩。细胞外信号调节激酶 1/2 和糖原合酶激酶 3β (GSK3β) 信号以不同的方式改变神经胶质蛋白支架网格。支架组织的差异同样影响突触 GABA 受体的扩散，表明神经胶质蛋白受体结合特性降低。在突触缩放的背景下，我们的结果确定了 GSK3β 信号通路在活动依赖性调节 extrasynaptic 受体表面贩运中的新作用，以及蛋白激酶 A 和钙/钙调蛋白依赖性蛋白激酶 IIα 通路在促进突触受体适应中的作用。
