In the central nervous system (CNS), NMDA receptors (NMDAR), part of the ionotropic glutamate receptors family, mediate the majority of fast excitatory neuronal transmission. By allowing calcium influx into neuronal cells and subsequent activation of signaling pathways, NMDAR play a central role in synaptic plasticity events that occur during development and underly cognition and memory processes. Recent advances in super resolution microscopy have revealed unexpected dimensions of NMDAR signaling beyond their ionotropic function, which contribute to synaptic physiology. Indeed, NMDAR adopt a precise and dynamically regulated nanoscale organization at synapses which regulates their plasticity and controls memory formation, thereby raising the question whether NMDAR synaptic organization can be of therapeutic interest. Moreover, competitive and non-competitive antagonists like open channel blockers (OCBs) elicit similar inhibition of NMDAR signaling but result in distinct behavioral outcomes, suggesting mechanisms independent of ion flux blocking. Using a combination of super resolution microscopy techniques and behavioral testing, we demonstrate that the non-competitive NMDAR antagonist ketamine enhances the synaptic trapping of receptors, and thereby alleviates anxiety/depressionlike behavioral deficits caused by autoantibodies from psychotic patients. We then examinedwhether these changes in NMDAR distribution at synapses may contribute to ketamine-elicited rearrangements in brain connectivity supporting its antidepressant properties. Major depressive disorder is a leading cause of disability worldwide and is believed to be the consequence of abnormal activity in key structures supporting mood and reward, namely cortico-meso-limbic structures. Current treatments, such as serotonin-based pharmacotherapies and psychotherapies, have a delayed onset of action and still up to one-third of patients are resistant. Thus, the recent discovery that a subanesthetic dose of ketamine induce a rapid-acting and sustained antidepressant effect has risen new hopes for the treatment of depression. Despite intense investigation, the mechanisms through which ketamine acts on NMDAR signaling within the cortico-meso-limbic network to produce its antidepressant effect remain unclear. To address this, we have developed a multi-level approach combining single-molecule imaging to monitor NMDAR synaptic redistributions and detection of immediate early gene expression in a pharmacological model of depression using light-sheet microscopy to identify network rearrangements induced by ketamine. Among all existing depression model, experiments were performed on a pharmacological model using corticosterone (CORT). A battery of behavioral tests was performed to evaluate ketamine impact on different modalities of the depression-like phenotype. We then assessed activity changes and network rearrangements at early (90 min)and later (24 hours) stages of ketamine antidepressant effect establishment. Parallel singleparticle tracking using photoactivated localization microscopy (PALM) experiments were performed on cortical neurons chronically incubated with corticosterone to examine changes in GluN2A-NMDAR and GluN2B-NMDAR organization at synapses, 90 min or 24 hours after ketamine. Overall, we provide new molecular mechanisms supporting ketamine-elicited behavioral changes, offering NMDAR synaptic distribution manipulation as a therapeutic strategy for both autoantibody-induced pathological deficits and depressive-associated deficits.