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.

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody

“…These effects are associated with a disruption of the normal interaction between the NMDAR and Ephrin‐B2 (EphB2) receptor at the synapse 10, 11. Consistently, anti‐NMDAR antibodies selectively decreased NMDAR‐mediated miniature excitatory postsynaptic currents (mEPSC) without affecting α ‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPA‐R)‐mediated mEPSCs in cultured rat hippocampal neurons 8, 9.…”

NMDA receptor encephalitis and other antibody-mediated disorders of the synapse

“…17 At the synapse, the antibodies disrupt the interaction between NMDAR and Ephrin type B2 receptor (EphB2). 39 The EphB2 receptor is a member of a family of receptor tyrosine kinases that modulate long-term potentiation (LTP) through their interaction with NMDAR and stabilization and clustering of this receptor in the postsynaptic membrane. 40,41 The disruption of this interaction results in displacement of NMDAR to extrasynaptic sites followed by internalization.…”

Human neurexin-3α antibodies associate with encephalitis and alter synapse development

“…First, they define the disorder as autoimmune regardless of a response to immunotherapy; second, they support the use of second-line immunotherapies or maintenance of intensive care if needed 5 ; and finally, there is evidence that most of the antibodies are pathogenic. 6 Some antibodies alter the surface dynamics of the cognate receptors causing their internalization (e.g., NMDAR 7,8 or AMPA receptor 9 ), while others block receptor function without altering its surface density (e.g., GABAb receptor 10 ). We report the clinical and immunologic features of a novel form of autoimmune encephalitis in which the antibodies target neurexin-3a, a presynaptic cell adhesion molecule with critical roles in synapse development and function.…”