Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis.
Brain. 2012-04-27; 135(5): 1606-1621
DOI: 10.1093/brain/aws092
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1. Brain. 2012 May;135(Pt 5):1606-21. doi: 10.1093/brain/aws092.
Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA
encephalitis.
Mikasova L(1), De Rossi P, Bouchet D, Georges F, Rogemond V, Didelot A, Meissirel
C, Honnorat J, Groc L.
Author information:
(1)CNRS, Interdisciplinary Institute for Neurosciences UMR 5297, Universite de
Bordeaux, 146 rue Leo Saignat, Bordeaux, France.
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.
DOI: 10.1093/brain/aws092
PMID: 22544902 [Indexed for MEDLINE]