Ephrin-B2 prevents N-methyl-D-aspartate receptor antibody effects on memory and neuroplasticity
Ann Neurol.. 2016-08-02; 80(3): 388-400
DOI: 10.1002/ana.24721
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Planagumà J(1), Haselmann H(2)(3), Mannara F(1), Petit-Pedrol M(1), Grünewald B(2)(3), Aguilar E(1), Röpke L(2), Martín-García E(4), Titulaer MJ(5), Jercog P(1), Graus F(1)(6), Maldonado R(4), Geis C(2)(3), Dalmau J(7)(8)(9)(10).
Author information:
(1)Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
(2)Hans-Berger Department of Neurology, Jena University Hospital, Jena, Germany.
(3)Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
(4)Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.
(5)Erasmus Medical Center, Rotterdam, The Netherlands.
(6)Servei de Neurologia, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
(7)Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain. .
(8)Department of Neurology, University of Pennsylvania, Philadelphia, PA. .
(9)Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER). .
(10)Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. .
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.
© 2016 American Neurological Association.