Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China.
Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China.
Cell Rep. 2023 Mar 28;42(3):112233. doi: 10.1016/j.celrep.2023.112233. Epub 2023 Mar 8.
Synaptotagmin III (Syt3) is a Ca-dependent membrane-traffic protein that is highly concentrated in synaptic plasma membranes and affects synaptic plasticity by regulating post-synaptic receptor endocytosis. Here, we show that Syt3 is upregulated in the penumbra after ischemia/reperfusion (I/R) injury. Knockdown of Syt3 protects against I/R injury, promotes recovery of motor function, and inhibits cognitive decline. Overexpression of Syt3 exerts the opposite effects. Mechanistically, I/R injury augments Syt3-GluA2 interactions, decreases GluA2 surface expression, and promotes the formation of Ca-permeable AMPA receptors (CP-AMPARs). Using a CP-AMPAR antagonist or dissociating the Syt3-GluA2 complex via TAT-GluA2-3Y peptide promotes recovery from neurological impairments and improves cognitive function. Furthermore, Syt3 knockout mice are resistant to cerebral ischemia because they show high-level expression of surface GluA2 and low-level expression of CP-AMPARs after I/R. Our results indicate that Syt3-GluA2 interactions, which regulate the formation of CP-AMPARs, may be a therapeutic target for ischemic insults.
突触融合蛋白 III（Syt3）是一种 Ca2+依赖性的膜转运蛋白，高度集中在突触质膜中，通过调节突触后受体内吞作用来影响突触可塑性。在这里，我们表明 Syt3 在缺血/再灌注（I/R）损伤后的半影区上调。Syt3 的敲低可防止 I/R 损伤，促进运动功能的恢复，并抑制认知能力下降。Syt3 的过表达则产生相反的效果。在机制上，I/R 损伤增强了 Syt3-GluA2 的相互作用，减少了 GluA2 的表面表达，并促进了 Ca2+通透性 AMPA 受体（CP-AMPAR）的形成。使用 CP-AMPAR 拮抗剂或通过 TAT-GluA2-3Y 肽解离 Syt3-GluA2 复合物可促进神经损伤的恢复并改善认知功能。此外，Syt3 敲除小鼠对脑缺血具有抗性，因为它们在 I/R 后表现出高水平的表面 GluA2 表达和低水平的 CP-AMPAR 表达。我们的结果表明，调节 CP-AMPAR 形成的 Syt3-GluA2 相互作用可能是缺血性损伤的治疗靶点。
