tetrodotoxin and 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.

Topics: 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