Detailed morphological analysis of rat hippocampi treated with CSF autoantibodies from patients with anti-NMDAR encephalitis discloses two distinct types of immunostaining patterns

Anti-NMDA receptor encephalitis was first described about thirteen years ago and has become one of the most important differential diagnoses for new-onset psychosis. The disease is mediated by autoantibodies against the subunit 1 of the N-methyl-D-aspartate receptor (NMDA-R1) in patients presenting with variable clinical symptoms. Patients often profit from immunmodulatory therapy, independent of their individual symptoms. In this study CSF samples as well as monoclonal antibodies derived from patients diagnosed with NMDA-R1 encephalitis were applied to rat hippocampus and visualized by immunocytochemistry. This reveals at least two distinct patterns of immunoreactivity. Antibodies from "pattern group 1" display the familiar pattern of NMDA-R1 distribution in the hippocampus reported in experiments with rabbit anti-NMDA-R1 antibodies. Neurons and primary dendrites in the CA1 and CA3 region show strongly stained cell bodies, in line with the predominant postsynaptic localization of the NMDA receptor in the brain. However, autoantibodies from "pattern group 2" show an inverse pattern, with no staining of the cell bodies and primary dendrites in CA1 and CA3 regions. Electron microscopic experiments disclose that autoantibodies of "pattern group 1 patients" bind to postsynaptic NMDA receptors, while those of "pattern group 2 patients" target presynaptic NMDA receptors. We describe one NMDA-receptor antibody giving staining comparable to rabbit anti-NMDA-R1 antibodies, raised against the C-terminus. In the highly heterogenous disease anti-NMDA-receptor 1 encephalitis we found evidence for at least two different subtypes. It will be very interesting to determine whether there also are two distinct clinical phenotypes.