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

Brain. 2012 May;135(Pt 5):1606-21. doi: 10.1093/brain/aws092.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Biophysics
  • Calcium / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Electric Stimulation
  • Embryo, Mammalian
  • Encephalitis / cerebrospinal fluid
  • Encephalitis / immunology*
  • Enzyme-Linked Immunosorbent Assay / methods
  • Ephrins / pharmacology
  • Excitatory Amino Acid Agents
  • Female
  • Hippocampus / cytology
  • Humans
  • Immunoglobulin G / blood
  • Immunoglobulin G / cerebrospinal fluid*
  • Immunoglobulin G / pharmacology
  • Immunoprecipitation / methods
  • Long-Term Potentiation / physiology
  • Male
  • Mice
  • Middle Aged
  • Neurons / drug effects
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Photobleaching
  • Protein Subunits / immunology
  • Protein Subunits / metabolism
  • Protein Transport / drug effects
  • Protein Transport / immunology
  • Rats
  • Receptor Cross-Talk / drug effects
  • Receptor Cross-Talk / immunology
  • Receptor Cross-Talk / physiology*
  • Receptors, Eph Family / metabolism*
  • Receptors, N-Methyl-D-Aspartate / immunology*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Sodium Channel Blockers / pharmacology
  • Tetrodotoxin / pharmacology
  • Tosyl Compounds / metabolism
  • Young Adult

Substances

  • Ephrins
  • Excitatory Amino Acid Agents
  • Immunoglobulin G
  • Protein Subunits
  • Receptors, N-Methyl-D-Aspartate
  • Sodium Channel Blockers
  • Tosyl Compounds
  • Tetrodotoxin
  • Receptors, Eph Family
  • Calcium