Tohoku J. Exp. Med., 2015 December, 237(4)

Induction of Memory Deficit in Mice with Chronic Exposure to Cerebrospinal Fluid from Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis

YONGZHI LI,^1,2,3 KEIKO TANAKA,^1,2 LI WANG,⁴ YASUHITO ISHIGAKI¹ and NOBUO KATO⁴

¹Department of Life Science, Medical Research Institute, Kanazawa Medical University, Kahoku-gun, Ishikawa, Japan
²Department of Neurology, Kanazawa Medical University, Kahoku-gun, Ishikawa, Japan
³Department of Urology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
⁴Department of Physiology, Kanazawa Medical University, Kahoku-gun, Ishikawa, Japan

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is now widely recognized and the patients with this disease show prominent psychiatric symptoms followed by seizures, respiratory failure, involuntary movement, autonomic instability, and amnesia. The anti-NMDAR antibody titer coincides with disease activity, and antibody-deprivation treatment ameliorates neurological symptoms. Previous studies have shown that clusters of NMDARs on the neuronal surface decrease in density upon incubation with the cerebrospinal fluid from patients (NMDAR-CSF), and that the induction of long-term potentiation, a cellular mechanism underlie learning and memory processes, was suppressed with NMDAR-CSF. In this study, we exposed mice to NMDAR-CSF in an attempt to reproduce the human symptoms in mice. CSF was continuously administered via a cannula placed in the lateral ventricle of the mouse that connected to an osmotic pump transplanted in the back of the mouse. From day 8-18, we evaluated the behavior of the mice using standardized tests that were performed serially. Mice exposed to NMDAR-CSF showed impaired spatial memory, as detected with the Morris water maze test. Brain tissue from mice with memory disturbances had decreased content of NMDAR protein in the hippocampal area shown by immunohistochemistry, which is consistent with the anti-NMDAR antibodies affect the expression and function of NMDARs, resulting in anti-NMDAR encephalitis-like symptoms. Also, the mice treated with the NMDAR-CSF did not show inflammatory cell infiltration or neuron loss in their brain tissue and this lack of nervous tissue destruction is encouraging as it is consistent with the idea that this disease can be treated through immunotherapy.

keywords —— amnesia; anti-NMDAR encephalitis; autoantibodies; Morris water maze test; mouse model

© 2015 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2015, 237, 329-338

Correspondence: Keiko Tanaka, M.D., Ph.D., Department of Life Science, Medical Research Institute and Department of Neurology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan.

e-mail: k-tana20@kanazawa-med.ac.jp