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Published on: March 16, 2016
d-serine prevents cognitive impairment in a mouse model of NMDAR encephalitis
Hanyu Luo1, Ziyao Han1, Jiaxin Yang1
1Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China.
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.
