title: 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.
authors.affiliation: CNRS, Interdisciplinary Institute for Neurosciences UMR 5297, Universite de Bordeaux, 146 rue Leo Saignat, Bordeaux, France.
authors.forename: Lenka
authors.initials: L
authors.lastname: Mikasova
authors.forename: Pierre
authors.initials: P
authors.lastname: De Rossi
authors.forename: Delphine
authors.initials: D
authors.lastname: Bouchet
authors.forename: François
authors.initials: F
authors.lastname: Georges
authors.forename: Véronique
authors.initials: V
authors.lastname: Rogemond
authors.forename: Adrien
authors.initials: A
authors.lastname: Didelot
authors.forename: Claire
authors.initials: C
authors.lastname: Meissirel
authors.forename: Jérôme
authors.initials: J
authors.lastname: Honnorat
authors.forename: Laurent
authors.initials: L
authors.lastname: Groc
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D004660:Encephalitis / Q000134:cerebrospinal fluid / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D036342:Ephrins / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents; D005260:Female; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000134:cerebrospinal fluid* / Q000494:pharmacology; D047468:Immunoprecipitation / Q000379:methods; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D038761:Photobleaching; D021122:Protein Subunits / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D051381:Rats; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D036081:Receptors, Eph Family / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology* / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014105:Tosyl Compounds / Q000378:metabolism; D055815:Young Adult
chemical_list: D036342:Ephrins; D018683:Excitatory Amino Acid Agents; D007074:Immunoglobulin G; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D026941:Sodium Channel Blockers; D014105:Tosyl Compounds; D013779:Tetrodotoxin; D036081:Receptors, Eph Family; D002118:Calcium