Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesia, and seizures. However, the underlying mechanisms of this disease remain unclear, in part because of a lack of suitable animal models. Methods This study describes a novel female C57BL/6 mouse model of anti-NMDAR encephalitis that was induced by active immunization against NMDARs using an amino terminal domain (ATD) peptide from the GluN1 subunit (GluN1356–385). Results Twelve weeks after immunization, the immunized mice showed significant memory loss. Furthermore, antibodies from the cerebrospinal fluid of immunized mice decreased the surface NMDAR cluster density in hippocampal neurons which was similar to the effect induced by the anti-NMDAR encephalitis patients’ antibodies. Immunization also impaired long-term potentiation at Schaffer collateral–CA1 synapses and reduced NMDAR-induced calcium influx. Conclusion We established a novel anti-NMDAR encephalitis model using active immunization with peptide GluN1356–385 targeting the ATD of GluN1. This novel model may allow further research into the pathogenesis of anti-NMDAR encephalitis and aid in the development of new therapies for this disease.

Anti-N-methyl-D-aspartate receptor (NMDA) receptor encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesias, and seizures. Ectopic expression of NMDA receptors associated with ovarian teratoma is thought to mediate the initial autoimmune response against NMDA receptor encephalitis. Due to the lack of suitable animal models, the underlying mechanism of the disease remains unclear. This study described a new mice model of active immunization against the NMDA receptor with amino-terminal domain (ATD) peptides. After 12 weeks of immunization, mice were showed significant behavioral disorders and memory loss. Antibodies from CSF of immunized mice decreased surface NMDAR cluster density on hippocampus neurons. It also impaired the LTP induced at the Schaffer collateral to CA1 synapse and reduced NMDA receptors-induced calcium influx. The new model may help further research into the pathogenesis of the disease and the development of potential new therapies.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesia, and seizures. However, the underlying mechanisms of this disease remain unclear, in part because of a lack of suitable animal models. This study describes a novel mouse model of anti-NMDAR encephalitis that was induced by active immunization against NMDARs using amino-terminal domain peptides. After 12 weeks of immunization, the mice showed significant behavioral disorders and memory loss. Furthermore, antibodies from the cerebrospinal fluid of immunized mice lowered the surface NMDAR cluster density in hippocampal neurons. Immunization also impaired long-term potentiation at Schaffer collateral–CA1 synapses and reduced NMDAR-induced calcium influx. This novel mouse model may allow further research into the pathogenesis of anti-NMDAR encephalitis and aid in the development of new therapies for this disease.