Ephrin-B2 prevents N-methyl-D-aspartate receptor antibody effects on memory and neuroplasticity

被引:132
|
作者
Planaguma, Jesus [1 ]
Haselmann, Holger [2 ,3 ]
Mannara, Francesco [1 ]
Petit-Pedrol, Mar [1 ]
Gruenewald, Benedikt [2 ,3 ]
Aguilar, Esther [1 ]
Roepke, Luise [2 ]
Martin-Garcia, Elena [4 ]
Titulaer, Maarten J. [5 ]
Jercog, Pablo [1 ]
Graus, Francesc [1 ,6 ]
Maldonado, Rafael [4 ]
Geis, Christian [2 ,3 ]
Dalmau, Josep [1 ,7 ,8 ,9 ]
机构
[1] Univ Barcelona, Hosp Clin, IDIBAPS, Barcelona, Spain
[2] Jena Univ Hosp, Hans Berger Dept Neurol, Jena, Germany
[3] Jena Univ Hosp, CSCC, Jena, Germany
[4] Univ Pompeu Fabra, Fac Ciencies Salut & Vida, Lab Neurofarmacol, Barcelona, Spain
[5] Erasmus MC, Rotterdam, Netherlands
[6] Univ Barcelona, Hosp Clin, Serv Neurol, Barcelona, Spain
[7] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA
[8] CIBERER, Barcelona, Spain
[9] ICREA, Barcelona, Spain
关键词
HIPPOCAMPAL SYNAPTIC PLASTICITY; NMDAR ENCEPHALITIS; CASE SERIES; MECHANISMS; CA1; STIMULATION; BEHAVIOR; BRAIN; LONG; LTP;
D O I
10.1002/ana.24721
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
ObjectiveTo demonstrate that ephrin-B2 (the ligand of EphB2 receptor) antagonizes the pathogenic effects of patients' N-methyl-D-aspartate receptor (NMDAR) antibodies on memory and synaptic plasticity. MethodsOne hundred twenty-two C57BL/6J mice infused with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, with or without ephrin-B2, were investigated. CSF was infused through ventricular catheters connected to subcutaneous osmotic pumps over 14 days. Memory, behavioral tasks, locomotor activity, presence of human antibodies specifically bound to hippocampal NMDAR, and antibody effects on the density of cell-surface and synaptic NMDAR and EphB2 were examined at different time points using reported techniques. Short- and long-term synaptic plasticity were determined in acute brain sections; the Schaffer collateral pathway was stimulated and the field excitatory postsynaptic potentials were recorded in the CA1 region of the hippocampus. ResultsMice infused with patients' CSF, but not control CSF, developed progressive memory deficit and depressive-like behavior along with deposits of NMDAR antibodies in the hippocampus. These findings were associated with a decrease of the density of cell-surface and synaptic NMDAR and EphB2, and marked impairment of long-term synaptic plasticity without altering short-term plasticity. Administration of ephrin-B2 prevented the pathogenic effects of the antibodies in all the investigated paradigms assessing memory, depressive-like behavior, density of cell-surface and synaptic NMDAR and EphB2, and long-term synaptic plasticity. InterpretationAdministration of ephrin-B2 prevents the pathogenic effects of anti-NMDAR encephalitis antibodies on memory and behavior, levels of cell-surface NMDAR, and synaptic plasticity. These findings reveal a strategy beyond immunotherapy to antagonize patients' antibody effects. Ann Neurol 2016;80:388-400
引用
收藏
页码:388 / 400
页数:13
相关论文
共 50 条
  • [1] The N-Methyl-D-Aspartate Receptor: Memory, Madness, and More
    Ramirez, Alejandro
    Arbuckle, Melissa R.
    BIOLOGICAL PSYCHIATRY, 2017, 82 (01) : E1 - E3
  • [2] In vitro effects of a human monoclonal antibody against the N-methyl-D-aspartate receptor
    Dalmau, Josep
    BRAIN, 2017, 140
  • [3] In vitro effects of a human monoclonal antibody against the N-methyl-D-aspartate receptor
    Dalmau, Josep
    BRAIN, 2017, 140 (02)
  • [4] N-methyl-D-aspartate receptor antibody-mediated encephalitis
    Mehta, Sachin
    Szawarski, Piotr
    Swayne, Orlando B.
    Kullmann, Dimitri M.
    Howell, David C. J.
    BRITISH JOURNAL OF HOSPITAL MEDICINE, 2012, 73 (08) : 472 - 473
  • [5] GLUTATHIONE PREVENTS N-METHYL-D-ASPARTATE RECEPTOR-MEDIATED NEUROTOXICITY
    LEVY, DI
    SUCHER, NJ
    LIPTON, SA
    NEUROREPORT, 1991, 2 (06) : 345 - 347
  • [6] Reply: In vitro effects of a human monoclonal antibody against the N-methyl-D-aspartate receptor
    Kreye, Jakob
    Wenke, Nina K.
    Garner, Craig C.
    Wardemann, Hedda
    Pruess, Harald
    BRAIN, 2017, 140 (02)
  • [7] Reply: In vitro effects of a human monoclonal antibody against the N-methyl-D-aspartate receptor
    Kreye, Jakob
    Wenke, Nina K.
    Garner, Craig C.
    Wardemann, Hedda
    Pruess, Harald
    BRAIN, 2017, 140
  • [8] THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX
    WILLIAMS, M
    LOO, PA
    MURPHY, DE
    BRAUNWALDER, AF
    JARVIS, MF
    SILLS, MA
    JOURNAL OF RECEPTOR RESEARCH, 1988, 8 (1-4): : 195 - 203
  • [9] The N-methyl-D-aspartate receptor and schizophrenia
    Strous, RD
    Javitt, DC
    ISRAEL JOURNAL OF MEDICAL SCIENCES, 1996, 32 (05): : 275 - 281
  • [10] TEMPERATURE DEPENDENCE OF N-METHYL-D-ASPARTATE RECEPTOR CHANNELS AND N-METHYL-D-ASPARTATE RECEPTOR EXCITATORY POSTSYNAPTIC CURRENTS
    Korinek, M.
    Sedlacek, M.
    Cais, O.
    Dittert, I.
    Vyklicky, L., Jr.
    NEUROSCIENCE, 2010, 165 (03) : 736 - 748