d-serine prevents cognitive impairment in a mouse model of NMDAR encephalitis

Abstract

Objective

Despite effective immunotherapy, many patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis continue to have persistent cognitive deficits. This study investigated whether d-serine administration can ameliorate cognitive impairment in a mouse model of anti-NMDAR encephalitis.

Methods

Mice received continuous intracerebroventricular infusions of purified IgG isolated from pooled cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis or non-inflammatory controls for 14 days. During the same period, mice were given daily intraperitoneal injections of d-serine or saline. Cognitive function and hippocampal synaptic plasticity were evaluated using a battery of behavioral tests and long-term potentiation (LTP) recordings. Western blotting and immunofluorescence staining were used to evaluate hippocampal NMDAR clustering and activation of the CaMKII/ERK/CREB pathway.

Results

After 14 days, mice infused with patient-derived anti-NMDAR antibodies showed significant memory impairment and reduced hippocampal LTP. These deficits were markedly attenuated by concurrent d-serine treatment. Patient-derived anti-NMDAR antibodies reduced synaptic NMDAR clusters and membrane NMDAR1 expression in hippocampus, whereas d-serine administration produced only a modest, non-significant increase in these measures. In contrast, d-serine significantly restored phosphorylation of CaMKII, ERK, and CREB that was suppressed by anti-NMDAR antibodies.

Conclusion

d-serine effectively ameliorates cognitive impairment induced by anti-NMDAR antibodies, likely by restoring NMDAR-mediated CaMKII/ERK/CREB signaling. These findings support d-serine as a potential adjunct to immunotherapy for patients with anti-NMDAR encephalitis.