Surface dynamics of GluN2B-NMDA receptors controls plasticity of maturing glutamate synapses

Abstract NMDA-type glutamate receptors (NMDAR) are central actors in the plasticity of excitatory synapses. During adaptive processes, the number and composition of synaptic NMDAR can be rapidly modified, as in neonatal hippocampal synapses where a switch from predominant GluN2B- to GluN2A-containing receptors is observed after the induction of long-term potentiation (LTP). However, the cellular pathways by which surface NMDAR subtypes are dynamically regulated during activity-dependent synaptic adaptations remain poorly understood. Using a combination of high-resolution single nanoparticle imaging and electrophysiology, we show here that GluN2B-NMDAR are dynamically redistributed away from glutamate synapses through increased lateral diffusion during LTP in immature neurons. Strikingly, preventing this activity-dependent GluN2B-NMDAR surface redistribution through cross-linking, either with commercial or with autoimmune anti-NMDA antibodies from patient with neuropsychiatric symptoms, affects the dynamics and spine accumulation of CaMKII and impairs LTP. Interestingly, the same impairments are observed when expressing a mutant of GluN2B-NMDAR unable to bind CaMKII. We thus uncover a non-canonical mechanism by which GluN2B-NMDAR surface dynamics plays a critical role in the plasticity of maturing synapses through a direct interplay with CaMKII. Synopsis image Long-term potentiation in immature hippocampal neurons requires glutamate receptor lateral diffusion and CaMKII recruitment, a process that can be blocked by autoimmune anti-NMDAR antibodies from patients with neuropsychiatric symptoms. In the hippocampus, postsynaptic NMDA receptor surface dynamics is locally regulated during plasticity. GluN2B-NMDA receptor surface dynamics is required for synaptic long-term potentiation. Surface GluN2B-NMDA receptor and CAMKII constantly influence each other. Decreased surface NMDA receptor dynamics, and thus impaired synaptic long-term potentiation, is likely the basis of cognitive symptoms in anti-NMDA receptor autoimmune disorder.