A juvenile mouse model of anti-N-methyl-D-aspartate receptor encephalitis by active immunization

Abstract

IntroductionAnti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis, and it is associated with psychosis, dyskinesia, and seizures. Anti-NMDAR encephalitis (NMDARE) in juveniles and adults presents different clinical charactreistics. However, the pathogenesis of juvenile anti-NMDAR encephalitis remains unclear, partly because of a lack of suitable animal models.MethodsWe developed a model of juvenile anti-NMDAR encephalitis using active immunization with an amino terminal domain peptide from the GluN1 subunit (GluN1356 − 385) against NMDARs in 3-week-old female C57BL/6J mice.ResultsImmunofluorescence staining suggested that autoantibody levels in the hippocampus increased, and HEK-293T cells staining identified the target of the autoantibodies as GluN1, suggesting that GluN1-specific immunoglobulin G was successfully induced. Behavior assessment showed that the mice suffered significant cognition impairment and sociability reduction, which is similar to what is observed in patients affected by anti-NMDAR encephalitis. The mice also exhibited impaired long-term potentiation in hippocampal CA1. Pilocarpine-induced epilepsy was more severe and had a longer duration, while no spontaneous seizures were observed.ConclusionThe juvenile mouse model for anti-NMDAR encephalitis is of great importance to investigate the pathological mechanism and therapeutic strategies for the disease, and could accelerate the study of autoimmune encephalitis.

Mechanisms of autoimmune encephalitis

“…Overall, both passive and active immunization models have demonstrated antibody-mediated molecular effects and reproduced some of the main behavioral and memory changes observed in patients with antibody-mediated encephalitides [9–18,21,22,23 ▪ ,26,30].…”

“…Since the role of inflammatory and T cell mediated mechanisms is unclear in NMDAR encephalitis [107 ▪ ,113], several studies have focused on active immunization models [19–22,23 ▪ ,24–26]. In one model, mice were immunized using purified GluN1/GluN2B NMDAR embedded in liposomes, resulting in a fulminant encephalitis with several symptoms of the acute phase of NMDAR encephalitis, and antibodies against epitope regions other than the amino-terminal domain of the GluN1 subunit (main region involved in the human disease) [19].…”

“…In one model, mice were immunized using purified GluN1/GluN2B NMDAR embedded in liposomes, resulting in a fulminant encephalitis with several symptoms of the acute phase of NMDAR encephalitis, and antibodies against epitope regions other than the amino-terminal domain of the GluN1 subunit (main region involved in the human disease) [19]. Other studies using GluN1 peptides resulted in behavioral and memory deficits along with changes suggesting impairment of the function or density of NMDARs [20–22,23 ▪ ,25]. However, many limitations are still present in the current models of active immunization, not only at the neurobiology or immunobiology levels but also at the disease level, such as the limited modeling of the protracted course of cognitive or psychiatric symptoms observed in humans.…”