Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction
Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction
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DOI：
10.1016/j.neuron.2018.07.048
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发表时间：
2018-10-10
期刊：
影响因子：
16.2
通讯作者：
Geis, Christian
中科院分区：
文献类型：
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作者：
Haselmann, Holger;Mannara, Francesco;Geis, Christian
AMPA受体对于CNS中的快速兴奋性传递是必需的。在患有自身免疫性脑炎和海马功能严重缺陷的人中已经鉴定出AMPA受体的自身抗体。在这里，结合电生理学和高分辨率成像与神经元培养制剂和被动转移模型在野生型和GluA1基因敲除小鼠，我们分析如何特定的人类自身抗体对AMPA受体亚基GluA2影响受体的功能和组成，突触传递和可塑性。抗GluA2抗体诱导受体内化和突触含GluA2的AMPAR减少，随后是突触非GluA2 AMPAR的补偿性ryanodine受体依赖性掺入。此外，人类致病性抗GluA2抗体对小鼠的应用损害体外长期突触可塑性，并影响体内学习和记忆。我们的研究结果确定了AMPA受体亚单位的特定免疫神经元重排，提供了一个框架来解释疾病症状。
AMPA receptors are essential for fast excitatory transmission in the CNS. Autoantibodies to AMPA receptors have been identified in humans with autoimmune encephalitis and severe defects of hippocampal function. Here, combining electrophysiology and high-resolution imaging with neuronal culture preparations and passive-transfer models in wild-type and GluA1-knockout mice, we analyze how specific human autoantibodies against the AMPA receptor subunit GluA2 affect receptor function and composition, synaptic transmission, and plasticity. Anti-GluA2 antibodies induce receptor internalization and a reduction of synaptic GluA2-containing AMPARs followed by compensatory ryanodine receptor-dependent incorporation of synaptic non-GluA2 AMPARs. Furthermore, application of human pathogenic anti-GluA2 antibodies to mice impairs long-term synaptic plasticity in vitro and affects learning and memory in vivo. Our results identify a specific immune-neuronal rearrangement of AMPA receptor sub-units, providing a framework to explain disease symptoms.