Autoantibodies against neuronal membrane proteins can manifest in autoimmune encephalitis, inducing seizures, cognitive dysfunction and psychosis. Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is the most dominant autoimmune encephalitis; however, insights into how autoantibodies recognize and alter receptor functions remain limited. Here we determined structures of human and rat NMDARs bound to three distinct patient-derived antibodies using single-particle electron cryo-microscopy. These antibodies bind different regions within the amino-terminal domain of the GluN1 subunit. Through electrophysiology, we show that all three autoantibodies acutely and directly reduced NMDAR channel functions in primary neurons. Antibodies show different stoichiometry of binding and antibody–receptor complex formation, which in one antibody, 003-102, also results in reduced synaptic localization of NMDARs. These studies demonstrate mechanisms of diverse epitope recognition and direct channel regulation of anti-NMDAR autoantibodies underlying autoimmune encephalitis.

针对神经元膜蛋白的自身抗体可表现为自身免疫性脑炎，诱发癫痫发作、认知功能障碍和精神病。抗 N-甲基-d-天冬氨酸受体 （NMDAR） 脑炎是最主要的自身免疫性脑炎;然而，关于自身抗体如何识别和改变受体功能的见解仍然有限。在这里，我们使用单颗粒电子冷冻显微镜确定了与三种不同的患者来源抗体结合的人和大鼠 NMDAR 的结构。这些抗体结合 GluN1 亚基氨基末端结构域内的不同区域。通过电生理学，我们表明所有三种自身抗体都急性和直接地降低了原代神经元中的 NMDAR 通道功能。抗体显示出不同的结合和抗体-受体复合物形成的化学计量，在一种抗体 003-102 中，这也导致 NMDAR 的突触定位降低。这些研究表明了自身免疫性脑炎潜在抗 NMDAR 自身抗体的不同表位识别和直接通道调节机制。