This study investigates the cellular and synaptic mechanisms underlying anti-NMDA receptor encephalitis, a severe and potentially lethal condition associated with autoantibodies to the NMDA receptor (NMDAR). The authors demonstrate that patients' NMDAR antibodies cause a selective and reversible decrease in NMDAR surface density and synaptic localization, which correlates with antibody titers. The mechanism involves selective antibody-mediated capping and internalization of surface NMDARs, as Fab fragments from patient antibodies do not decrease surface receptor density. In cultured rat hippocampal neurons, these antibodies specifically reduce synaptic NMDAR-mediated currents without affecting other glutamate receptors or synaptic proteins. In vivo studies in female Lewis rats show that patients' antibodies reduce NMDAR density in the hippocampus, similar to the decrease observed in autopsied patients. These findings establish the cellular mechanisms by which anti-NMDAR antibodies cause a specific, titer-dependent, and reversible loss of NMDARs, leading to learning, memory, and behavioral deficits in patients with anti-NMDAR encephalitis.This study investigates the cellular and synaptic mechanisms underlying anti-NMDA receptor encephalitis, a severe and potentially lethal condition associated with autoantibodies to the NMDA receptor (NMDAR). The authors demonstrate that patients' NMDAR antibodies cause a selective and reversible decrease in NMDAR surface density and synaptic localization, which correlates with antibody titers. The mechanism involves selective antibody-mediated capping and internalization of surface NMDARs, as Fab fragments from patient antibodies do not decrease surface receptor density. In cultured rat hippocampal neurons, these antibodies specifically reduce synaptic NMDAR-mediated currents without affecting other glutamate receptors or synaptic proteins. In vivo studies in female Lewis rats show that patients' antibodies reduce NMDAR density in the hippocampus, similar to the decrease observed in autopsied patients. These findings establish the cellular mechanisms by which anti-NMDAR antibodies cause a specific, titer-dependent, and reversible loss of NMDARs, leading to learning, memory, and behavioral deficits in patients with anti-NMDAR encephalitis.