Autoantibodies targeting neuronal membrane proteins can cause encephalitis, seizures, and severe behavioral abnormalities. While antibodies for several neuronal targets have been identified, structural details on how they regulate function are unknown. Here we determined cryo-electron microscopy structures of antibodies derived from an encephalitis patient bound to the γ-aminobutyric acid type A (GABA_A) receptor. These antibodies induced severe encephalitis by directly inhibiting GABA_A function, resulting in nervous-system hyperexcitability. The structures reveal mechanisms of GABA_A inhibition and pathology. One antibody directly competes with a neurotransmitter and locks the receptor in a resting-like state. The second antibody targets the subunit interface involved in binding benzodiazepines and antagonizes diazepam potentiation. We identify key residues in these antibodies involved in specificity and affinity and confirm structure-based hypotheses for functional effects using electrophysiology. Together these studies define mechanisms of direct functional antagonism of neurotransmission underlying autoimmune encephalitis in a human patient.

针对神经元膜蛋白的自身抗体可引起脑炎、癫痫发作和严重的行为异常。虽然已经确定了针对多个神经元靶标的抗体，但它们如何调节功能的结构细节尚不清楚。在这里，我们确定了来自脑炎患者的与 γ-氨基丁酸 A 型 (GABA _A ) 受体结合的抗体的冷冻电子显微镜结构。这些抗体通过直接抑制 GABA _A功能，导致神经系统过度兴奋，从而诱发严重脑炎。结构揭示了 GABA _{A的作用机制}抑制和病理学。一种抗体直接与神经递质竞争并将受体锁定在类似静息的状态。第二抗体靶向参与结合苯二氮卓类药物的亚基界面并拮抗地西泮的增强作用。我们鉴定了这些抗体中涉及特异性和亲和力的关键残基，并使用电生理学确认了基于结构的功能效应假设。这些研究共同定义了人类患者自身免疫性脑炎神经传递的直接功能拮抗机制。