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Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis

Lenka Mikasova, Pierre De Rossi, Delphine Bouchet, François Georges, Véronique Rogemond, Adrien Didelot, Claire Meissirel, Jérôme Honnorat, Laurent Groc
DOI: http://dx.doi.org/10.1093/brain/aws092 1606-1621 First published online: 28 April 2012

Summary

Autoimmune synaptic encephalitides are recently described human brain diseases leading to psychiatric and neurological syndromes through inappropriate brain–autoantibody interactions. The most frequent synaptic autoimmune encephalitis is associated with autoantibodies against extracellular domains of the glutamatergic N-methyl-d-aspartate receptor, with patients developing psychotic and neurological symptoms in an autoantibody titre-dependent manner. Although N-methyl-d-aspartate receptors are the primary target of these antibodies, the cellular and molecular pathway(s) that rapidly lead to N-methyl-d-aspartate receptor dysfunction remain poorly understood. In this report, we used a unique combination of high-resolution nanoparticle and bulk live imaging approaches to demonstrate that anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis strongly alter, in a time-dependent manner, the surface content and trafficking of GluN2-NMDA receptor subtypes. Autoantibodies laterally displaced surface GluN2A-NMDA receptors out of synapses and completely blocked synaptic plasticity. This loss of extrasynaptic and synaptic N-methyl-d-aspartate receptor is prevented both in vitro and in vivo, by the activation of EPHB2 receptors. Indeed, the anti-N-methyl-d-aspartate receptor autoantibodies weaken the interaction between the extracellular domains of the N-methyl-d-aspartate and Ephrin-B2 receptors. Together, we demonstrate that the anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis alter the dynamic retention of synaptic N-methyl-d-aspartate receptor through extracellular domain-dependent mechanism(s), shedding new light on the pathology of the neurological and psychiatric disorders observed in these patients and opening possible new therapeutic strategies.

  • glutamate signalling
  • lateral diffusion
  • high-resolution nanoparticle imaging
  • Abbreviations
    AMPAR
    alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
    EPHB2R
    Ephrin-B2 receptor
    GABA
    γ-aminobutyric acid
    IgG
    immunoglobulin G
    NMDA
    N-methyl-d-aspartate
    SEP
    super-ecliptic pHluorin
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