Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis.
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.
Mesh Terms:
Adult, Aged, Animals, Biophysics, Calcium, Cell Membrane, Cells, Cultured, Child, Child, Preschool, Electric Stimulation, Embryo, Mammalian, Encephalitis, Enzyme-Linked Immunosorbent Assay, Ephrins, Excitatory Amino Acid Agents, Female, Hippocampus, Humans, Immunoglobulin G, Immunoprecipitation, Long-Term Potentiation, Male, Mice, Middle Aged, Neurons, Patch-Clamp Techniques, Photobleaching, Protein Subunits, Protein Transport, Rats, Receptor Cross-Talk, Receptors, Eph Family, Receptors, N-Methyl-D-Aspartate, Sodium Channel Blockers, Tetrodotoxin, Tosyl Compounds, Young Adult
Adult, Aged, Animals, Biophysics, Calcium, Cell Membrane, Cells, Cultured, Child, Child, Preschool, Electric Stimulation, Embryo, Mammalian, Encephalitis, Enzyme-Linked Immunosorbent Assay, Ephrins, Excitatory Amino Acid Agents, Female, Hippocampus, Humans, Immunoglobulin G, Immunoprecipitation, Long-Term Potentiation, Male, Mice, Middle Aged, Neurons, Patch-Clamp Techniques, Photobleaching, Protein Subunits, Protein Transport, Rats, Receptor Cross-Talk, Receptors, Eph Family, Receptors, N-Methyl-D-Aspartate, Sodium Channel Blockers, Tetrodotoxin, Tosyl Compounds, Young Adult
Brain
Date: May. 01, 2012
PubMed ID: 22544902
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