Anti-NMDAR encephalitis induced in mice by active immunization with a peptide from the amino-terminal domain of the GluN1 subunit

Yuewen Ding,Haitao Wang,Yu Peng,Wei Xie,Jun Zhang,Zheye Zhou,Jinyu Chen,Wei Qiu,Honghao Wang

doi:10.1186/s12974-021-02107-0

Abstract

BackgroundAnti-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.MethodsThis 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).ResultsTwelve 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.ConclusionWe 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.

Highlights

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesia, and seizures
Detection of antigen specificity of peptide-induced autoantibodies To induce an active immune mouse model of antiNMDAR encephalitis, mice were immunized by subcutaneous injection with 200 μg of peptide emulsified in Complete Freund’s Adjuvant (Fig. 1a)
We found that only the GluN1356–385 peptide could induce Cerebrospinal fluid (CSF) autoantibodies that were specific for GluN1 (Fig. 1b)

Summary

Introduction

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesia, and seizures. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system (CNS) that predominantly affects young females. Antigens are taken up by antigen-presenting cells that travel to regional lymph nodes, and plasma cells produce antibodies (ABs) that later react with NMDARs in the brain, impairing blood-brain barrier permeability [5]. Previous studies have suggested that the pathogenicity of autoimmune ABs is a key mechanism of anti-NMDAR encephalitis [1, 6]. Reduced NMDAR expression can result in increased extracellular glutamate and affect the pons/medullary respiratory center [7]

Methods

Results

Conclusion