A juvenile mouse model of anti-N-methyl-D-aspartate receptor encephalitis by active immunization

Shuyu He; Chongyang Sun; Qian Zhu; Lin Li; Jianyu Huang; Ge Wu; Yi Cao; Jianxiang Liao; Yi Lu; Qiru Su; Sufang Lin; Xiaopeng Ma; Cheng Zhong

doi:10.3389/fnmol.2023.1211119

A juvenile mouse model of anti-N-methyl-D-aspartate receptor encephalitis by active immunization

Front Mol Neurosci. 2023 Sep 18:16:1211119. doi: 10.3389/fnmol.2023.1211119. eCollection 2023.

Authors

Shuyu He^#^{1

2

3}, Chongyang Sun^#^{1

4}, Qian Zhu^#^{1

2}, Lin Li², Jianyu Huang¹, Ge Wu^{1

4}, Yi Cao¹, Jianxiang Liao², Yi Lu¹, Qiru Su², Sufang Lin², Xiaopeng Ma², Cheng Zhong¹

Affiliations

¹ Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, CAS Key Laboratory of Brain Connectome and Manipulation, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institution, Shenzhen, China.
² Department of Clinical Research, Department of Neurology, Surgery Division, Epilepsy Center, Shenzhen Children's Hospital, Shenzhen, China.
³ Shenzhen Children's Hospital of China Medical University, Shenzhen, China.
⁴ University of Chinese Academy of Sciences, Beijing, China.

^# Contributed equally.

Abstract

Introduction: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis, and it is associated with psychosis, dyskinesia, and seizures. Anti-NMDAR encephalitis (NMDARE) in juveniles and adults presents different clinical charactreistics. However, the pathogenesis of juvenile anti-NMDAR encephalitis remains unclear, partly because of a lack of suitable animal models.

Methods: We developed a model of juvenile anti-NMDAR encephalitis using active immunization with an amino terminal domain peptide from the GluN1 subunit (GluN1_{356 - 385}) against NMDARs in 3-week-old female C57BL/6J mice.

Results: Immunofluorescence staining suggested that autoantibody levels in the hippocampus increased, and HEK-293T cells staining identified the target of the autoantibodies as GluN1, suggesting that GluN1-specific immunoglobulin G was successfully induced. Behavior assessment showed that the mice suffered significant cognition impairment and sociability reduction, which is similar to what is observed in patients affected by anti-NMDAR encephalitis. The mice also exhibited impaired long-term potentiation in hippocampal CA1. Pilocarpine-induced epilepsy was more severe and had a longer duration, while no spontaneous seizures were observed.

Conclusion: The juvenile mouse model for anti-NMDAR encephalitis is of great importance to investigate the pathological mechanism and therapeutic strategies for the disease, and could accelerate the study of autoimmune encephalitis.

Keywords: active immunization; anti-NMDAR encephalitis; cognitive deficits; epilepsy susceptibility; juvenile mouse model.

Grants and funding

This work was supported by National Science and Technology Innovation 2030—Brain Science and Brain-Like Intelligence Technology Major Project (2022ZD0209500), National Natural Science Foundation of China (Nos. 32171024, 31700921, 31871080, and 32071035), Guangdong High-level Hospital Construction Fund, Natural Science Fund of Guangdong Province (2022A1515010586), Guangdong Natural Science Fund for Distinguished Young Scholars (2020B1515020042), CAS Key Laboratory of Brain Connectome and Manipulation (2019DP173024), Shenzhen Government Basic Research Grant (JCYJ20200109150818777), and Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression (ZDSYS20220606100606014).