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

Planagumà, Jesús; Haselmann, Holger; Mannara, Francesco; Petit-Pedrol, Mar; Grünewald, Benedikt; Aguilar, Esther; Röpke, Luise; Martín García, Elena, 1975-; Titulaer, Maarten J.; Jercog, Pablo; Graus, Francesc; Maldonado, Rafael, 1961-; Geis, Christian; Dalmau, Josep

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

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dc.contributor.author Planagumà, Jesúsca
dc.contributor.author Haselmann, Holgerca
dc.contributor.author Mannara, Francescoca
dc.contributor.author Petit-Pedrol, Marca
dc.contributor.author Grünewald, Benediktca
dc.contributor.author Aguilar, Estherca
dc.contributor.author Röpke, Luiseca
dc.contributor.author Martín García, Elena, 1975-ca
dc.contributor.author Titulaer, Maarten J.ca
dc.contributor.author Jercog, Pabloca
dc.contributor.author Graus, Francescca
dc.contributor.author Maldonado, Rafael, 1961-ca
dc.contributor.author Geis, Christianca
dc.contributor.author Dalmau, Josepca
dc.date.accessioned 2017-04-20T07:19:34Z
dc.date.issued 2016
dc.description.abstract OBJECTIVE: To 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. METHODS: One 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. RESULTS: Mice 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. INTERPRETATION: Administration 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.
dc.description.sponsorship This study was supported, in part, by Instituto Carlos III/FEDER (FIS 15/00377 [to F.G.], FIS 14/00203 and CIBERER [to J.D.], and RETICS-RTA and RD12/0028/0023 [to R.M.]), NIH RO1NS077851 (to J.D.), MINECO (SAF2014-59648-P; to R.M.), European Commission (HEALTH-F2-2013-602891; to R.M.), Fundació Cellex (to J.D.), the Netherlands Organisation for Scientific Research (NWO, Veni incentive; to M.T.), an Erasmus MC fellowship (to M.T.), and the German Research Council (DFG; GE 2519/3-1 and CRC-TR 166/1 B2 [to C.G.])
dc.format.mimetype application/pdfca
dc.identifier.citation Planagumà J, Haselmann H, Mannara F, Petit-Pedrol M, Grünewald B, Aguilar E et al. Ephrin-B2 prevents N-methyl-D-aspartate receptor antibody effects on memory and neuroplasticity. Ann Neurol. 2016 Sep;80(3):388-400. DOI: 10.1002/ana.24721
dc.identifier.doi http://dx.doi.org/10.1002/ana.24721
dc.identifier.issn 0364-5134
dc.identifier.uri http://hdl.handle.net/10230/30843
dc.language.iso eng
dc.publisher Wileyca
dc.relation.ispartof Annals of Neurology. 2016 Sep;80(3):388-400
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/602891
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-59648-P
dc.rights This is the pre-peer reviewed version of the following article: Planagumà J, Haselmann H, Mannara F, Petit-Pedrol M, Grünewald B, Aguilar E et al. Ephrin-B2 prevents N-methyl-D-aspartate receptor antibody effects on memory and neuroplasticity. Ann Neurol. 2016 Sep; 80(3): 388-400, which has been published in final form at http://dx.doi.org/10.1002/ana.24721. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.subject.other Encefalitis
dc.subject.other Proteïnes
dc.title Ephrin-B2 prevents N-methyl-D-aspartate receptor antibody effects on memory and neuroplasticityca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/acceptedVersion

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