Séminaire externe Julien DUPUIS

Activity-dependent modulations of N-methyl-D-aspartate glutamate receptor (NMDAR) trapping and organization at synapses regulate excitatory neurotransmission and shape cognitive functions. While NMDAR synaptic destabilization has been associated with several neurological and psychiatric conditions, manipulating receptor trapping to assess its clinical relevance for the treatment of brain conditions remains a challenge. We show that ketamine – a dissociative anesthetic blocking the pore of NMDAR – and other clinically relevant NMDAR open channel blockers (OCBs) promote interactions between NMDAR and PDZ-domain-containing scaffolding proteins and enhance NMDAR trapping at synapses. We further expose that KET-elicited trapping enhancement can compensate for depletion in synaptic receptors triggered by autoantibodies from patients with anti-NMDAR encephalitis. Preventing synaptic depletion mitigates impairments in NMDAR-mediated CaMKII signaling and alleviates anxiety- and sensorimotor-gating-related behavioral deficits provoked by autoantibodies. Altogether, these findings reveal an unexpected dimension of OCB action and stress the potential of targeting receptor anchoring in NMDAR-related synaptopathies.