The NMDA Receptor Antibody Paradox: A Possible Approach to Developing Immunotherapies Targeting the NMDA Receptor.

N-methyl-D-aspartate receptors (NMDAR) play a key role in brain development and function, including contributing to the pathogenesis of many neurological disorders. Immunization against the GluN1 subunit of the NMDAR and the production of GluN1 antibodies is associated with neuroprotective and seizure-protective effects in rodent models of stroke and epilepsy, respectively. Whilst these data suggest the potential for the development of GluN1 antibody therapy, paradoxically GluN1 autoantibodies in humans are associated with the pathogenesis of the autoimmune disease anti-NMDA receptor encephalitis. This review discusses possible reasons for the differential effects of GluN1 antibodies on NMDAR physiology that could contribute to these phenotypes.