Anti-NMDA receptor encephalitis is a severe, potentially lethal, but treatable condition associated with autoantibodies targeting the NMDA receptor (NMDAR). These antibodies cause a selective and reversible decrease in NMDAR surface density and synaptic localization, which correlates with antibody titers. The mechanism involves antibody-mediated capping and internalization of surface NMDARs, as Fab fragments from these antibodies do not reduce surface receptor density, but cross-linking with anti-Fab antibodies recapitulates the decrease. Whole-cell patch-clamp recordings show that these antibodies specifically decrease synaptic NMDAR-mediated currents without affecting AMPA receptor-mediated currents. Other glutamate receptors and synaptic proteins, synapse number, dendritic spines, and cell survival are not affected. In female Lewis rats, NMDAR density is dramatically reduced in the hippocampus after infusion with patients' antibodies, 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. The disorder is characterized by prominent psychiatric and behavioral symptoms, rapid memory loss, seizures, abnormal movements, hypoventilation, and autonomic instability. It predominantly affects females, with a median age of 19 years. In 55% of adults, the disorder is triggered by the presence of a tumor, mostly an ovarian teratoma expressing NMDARs. Despite the severity of symptoms, 75% of patients recover after immunotherapy and tumor removal, while 25% are left with memory, cognitive, and motor deficits. Autoantibodies are present in patients' serum and CSF, with high concentrations in CSF. These antibodies recognize the N-terminal extracellular domain of the NR1 subunit of the NMDAR, suggesting an antibody-mediated pathogenesis. In vitro and in vivo studies show that patients' antibodies reduce surface and synaptic NMDAR density and function, likely underlying the learning, memory, and behavioral deficits observed in patients. Patients' antibodies do not affect the number of synapses or other synaptic components, and their effects are reversible when antibody titers decrease. The loss of NMDARs eliminates NMDAR-mediated synaptic function, resulting in the cognitive and behavioral deficits seen in the disorder. The reversible loss of NMDARs and resulting synaptic dysfunction may underlie the deficits of memory, behavior, and cognition in anti-NMDAR encephalitis. The disorder is characterized by frequent symptom reversibility, even in severe cases. Clinical outcomes correlate with antibody titers, which are often higher in CSF than serum due to intrathecal antibody synthesis. Analysis of the hippocampus of patients who died from the disorder showed a substantial decrease in NMDAR levels compared to age-matched, neurologically normal individuals. This decrease was comparable to that observed inAnti-NMDA receptor encephalitis is a severe, potentially lethal, but treatable condition associated with autoantibodies targeting the NMDA receptor (NMDAR). These antibodies cause a selective and reversible decrease in NMDAR surface density and synaptic localization, which correlates with antibody titers. The mechanism involves antibody-mediated capping and internalization of surface NMDARs, as Fab fragments from these antibodies do not reduce surface receptor density, but cross-linking with anti-Fab antibodies recapitulates the decrease. Whole-cell patch-clamp recordings show that these antibodies specifically decrease synaptic NMDAR-mediated currents without affecting AMPA receptor-mediated currents. Other glutamate receptors and synaptic proteins, synapse number, dendritic spines, and cell survival are not affected. In female Lewis rats, NMDAR density is dramatically reduced in the hippocampus after infusion with patients' antibodies, 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. The disorder is characterized by prominent psychiatric and behavioral symptoms, rapid memory loss, seizures, abnormal movements, hypoventilation, and autonomic instability. It predominantly affects females, with a median age of 19 years. In 55% of adults, the disorder is triggered by the presence of a tumor, mostly an ovarian teratoma expressing NMDARs. Despite the severity of symptoms, 75% of patients recover after immunotherapy and tumor removal, while 25% are left with memory, cognitive, and motor deficits. Autoantibodies are present in patients' serum and CSF, with high concentrations in CSF. These antibodies recognize the N-terminal extracellular domain of the NR1 subunit of the NMDAR, suggesting an antibody-mediated pathogenesis. In vitro and in vivo studies show that patients' antibodies reduce surface and synaptic NMDAR density and function, likely underlying the learning, memory, and behavioral deficits observed in patients. Patients' antibodies do not affect the number of synapses or other synaptic components, and their effects are reversible when antibody titers decrease. The loss of NMDARs eliminates NMDAR-mediated synaptic function, resulting in the cognitive and behavioral deficits seen in the disorder. The reversible loss of NMDARs and resulting synaptic dysfunction may underlie the deficits of memory, behavior, and cognition in anti-NMDAR encephalitis. The disorder is characterized by frequent symptom reversibility, even in severe cases. Clinical outcomes correlate with antibody titers, which are often higher in CSF than serum due to intrathecal antibody synthesis. Analysis of the hippocampus of patients who died from the disorder showed a substantial decrease in NMDAR levels compared to age-matched, neurologically normal individuals. This decrease was comparable to that observed in