From Behavior To Synapse: A Murine Model Of Passive Transfer Of Antibodies From Patients With Anti-NMDAR Encephalitis (S63.007)
Neurology(2014)
摘要
OBJECTIVE: To report an animal model of memory and behavioral deficits caused by antibodies from patients with anti-NMDAR encephalitis.
BACKGROUND: Patients with anti-NMDAR encephalitis develop prominent behavioral and memory deficits. We previously showed that patient’s antibodies cause a specific decrease of the density, synaptic localization, and function of NMDARs in cultures of neurons and rat brain. However, the confirmation of an antibody-mediated pathogenesis depends on modeling the symptoms in animals.
METHODS: C57/BL6 mice underwent infusion of patients’ or control CSF via intraventricular catheters connected subcutaneously to osmotic pumps (continuous infusion 0.5 µl/hour for 14 days). Memory (V-maze object recognition), anxiety (elevated plus maze), aggression (resident intruder), anhedonia (consumption of sucrose), depression (tail-suspension), and locomotor activity were assessed blindly on days 5, 13, 18, and 26. Brains from representative animals obtained at each time point were examined for antibody binding and effects on NMDAR using quantitative immunoblot and confocal microscopy.
RESULTS: Eighteen mice injected with patients’ CSF and 20 controls were included in the study. Compared with controls, the most dramatic effect was the progressive decrease of memory during the days of antibody injection (day 10: NMDAR 0.35±0.05 versus control 0.41±0.06; p 0.05). In addition, animals injected with patients’ CSF had more depressed behavior (NMDAR 187.00s±7.07 versus control 153.30s±9.76; p=0.006) and anhedonia (NMDAR 76.64±6.37 versus control 87.66±0.79; p=0.068). Brain studies showed that animals injected with patients’ CSF, but not control CSF, had NMDAR antibodies bound to hippocampus, along with a reversible decrease of the levels and synaptic localization of NMDAR (p=0.018).
CONCLUSIONS: Antibodies from patients with anti-NMDAR encephalitis cause memory and behavioral deficits related to antibody-mediated decrease of hippocampal NMDAR.
Study Supported by: Instituto Carlos III, FIS PI11/01780 (JD) and PI112/00611 (FG), and the NIH RO1NS077851 (JD), MH094741 (RB-G and JD)and Fundacio la Marato TV3 (101530 JD) Disclosure: Dr. Francesco has nothing to disclose. Dr. Gutierrez Cuesta has nothing to disclose. Dr. Leypoldt has received personal compensation for activities with Grifols as a speaker. Dr. Planaguma has nothing to disclose. Dr. Martin Garcia has nothing to disclose. Dr. Jain has nothing to disclose. Dr. Graus has nothing to disclose. Dr. Balice-Gordon has received personal compensation for activities with Pfizer, Inc. as an employee. Dr. Maldonado Lopez has nothing to disclose. Dr. Dalmau has received personal compensation in an editorial capacity for Up To Date. Dr. Dalmau has received royalty payments from Athena Diagnostics. Dr. Dalmau has received research support from Euroimmun.
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