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

Abstract : 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.
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https://hal.archives-ouvertes.fr/hal-01160045
Contributor : Francois Georges <>
Submitted on : Thursday, June 4, 2015 - 12:46:39 PM
Last modification on : Friday, April 17, 2020 - 1:45:47 AM

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Lenka Mikasova, Pierre de Rossi, Delphine Bouchet, François Georges, Véronique Rogemond, et al.. Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis.. Brain - A Journal of Neurology , Oxford University Press (OUP), 2012, 135 (Pt 5), pp.1606-21. ⟨10.1093/brain/aws092⟩. ⟨hal-01160045⟩

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