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出现在自身免疫性脑炎中，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，对自身抗体如何识别和改变受体功能的了解仍然有限。在这里，我们使用单粒子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，我们发现所有三种自身抗体均急剧且直接降低原代神经元中的 NMDAR 通道功能。抗体显示出不同的结合化学计量和抗体-受体复合物形成，其中一种抗体 003-102 也会导致 NMDAR 突触定位减少。这些研究证明了自身免疫性脑炎的抗 NMDAR 自身抗体的多种表位识别和直接通道调节机制。