Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an antibody-mediated autoimmune disorder characterized by neuroinflammation, synaptic dysfunction, and prominent cognitive impairment. While immunotherapies reduce antibody burden, cognitive recovery is often incomplete, suggesting that persistent neuronal dysfunction contributes to disease outcome. Here, we investigated the effects of D-serine, an endogenous NMDAR co-agonist, in a mouse model of anti-NMDAR encephalitis induced by active immunization with the GluN1₃₅₉–₃₇₈ peptide. Immunized mice exhibited sustained learning and memory deficits accompanied by hippocampal neuronal integrity, dendritic disruption, and decreased expression of synaptic proteins. D-serine administration during the established disease phase significantly improved cognitive performance, partially restored NMDAR1 expression, and ameliorated neuronal and synaptic alterations in the hippocampus. Proteomic analysis further revealed that D-serine was associated with the partial normalization of proteins involved in axonal development, synaptic transmission, and receptor-related signaling pathways. In parallel, GluN1₃₅₉–₃₇₈ immunization induced increased microglial density and activation-associated changes, while D-serine had limited effects on microglial abundance and morphology but attenuated TSPO expression within IBA1⁺ microglia. Together, these findings suggest that neuronal and synaptic alterations are key contributors to cognitive deficits in this model, and that D-serine may promote functional recovery primarily through modulation of neuronal and synaptic processes rather than through broad suppression of neuroinflammatory responses. Targeting neuronal resilience may therefore represent a complementary therapeutic strategy alongside immune modulation in anti-NMDAR encephalitis.
Yao et al. (2026) studied this question.