D-Serine May Ameliorate Hippocampal Synaptic Plasticity Impairment Induced by Patients' Anti-N-methyl-D-aspartate Receptor Antibodies in Mice

Objective: To establish a mouse model of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and assess the potential therapeutic benefits of D-serine supplementation in mitigating synaptic plasticity impairments induced by anti-NMDAR antibodies. Methods: Anti-NMDAR antibodies were purified from cerebrospinal fluid (CSF) samples of patients diagnosed with anti-NMDAR encephalitis and verified using a cell-based assay. CSF from patients with non-inflammatory neurological diseases served as the control. These antibodies were then injected intraventricularly into C57BL/6 mice. Forty-eight hours following the injection, mice were administered either D-serine (500 mg/kg) or sterile saline intraperitoneally for three consecutive days. Subsequent analyses included Western blotting, immunofluorescence, electrophysiological studies, and a series of behavioral tests to assess pathological changes caused by anti-NMDAR antibodies. Results: Mice injected with anti-NMDAR antibodies exhibited a significant reduction in hippocampal long-term potentiation compared to controls, which was notably ameliorated by D-serine treatment. Additionally, these mice displayed decreased levels of hippocampal membrane NMDAR1 protein and postsynaptic NMDAR1 density. However, D-serine administration did not significantly alter these conditions. Notably, no significant behavioral differences were observed between mice injected with anti-NMDAR antibodies and controls in open fields, elevated plus maze, novel object recognition, or Morris water maze tests. Conclusions: Our findings indicate that exogenous D-serine can improve hippocampal plasticity impairments caused by anti-NMDAR antibodies but does not reverse the decreased expression of NMDAR. Furthermore, a single intraventricular injection of patients' antibodies was insufficient to induce anti-NMDAR encephalitis-related behaviors in mice.