NMDA Receptor Mediated Mechanisms in the Post-Stroke Brain: From Physiology to Pathology

N-methyl-D-aspartate receptors (NMDARs) play a context-dependent role in ischemic stroke (IS), contributing to acute excitotoxic injury while also supporting subsequent neuroplasticity. This functional divergence has constrained the therapeutic efficacy of non-selective NMDAR antagonists. During the acute phase, neuronal injury is associated with the redistribution of NMDARs toward extrasynaptic sites and the activation of aberrant non-ionotropic signaling pathways. As the disease progresses, NMDAR-dependent signaling becomes increasingly involved in activity-dependent plasticity, including motor engram consolidation, dendritic remodeling, and large-scale network reorganization. Post-stroke cognitive impairment and depression are increasingly recognized as potential consequences of sustained NMDAR dysregulation, involving interactions with immune signaling and metabolic processes. These observations support a shift toward activity-dependent modulation of NMDAR function, in which neurotoxic signaling is selectively dissociated from physiological receptor activity. Emerging strategies aimed at subunit-specific modulation and disruption of pathological receptor complexes provide a basis for more targeted intervention. Preservation of physiological excitation–inhibition balance may therefore represent a key requirement for optimizing functional recovery after stroke.