NMDA receptor functions in health and disease: Old actor, new dimensions

• Published in: Neuron (Cambridge, Mass.) Mass.), 2023-08, Vol.111 (15), p.2312-2328
• Main Authors: Dupuis, Julien P., Nicole, Olivier, Groc, Laurent
• Format: Article
• Language: English
• Subjects: Cognitive science; Life Sciences; Neurobiology; Neurons and Cognition; Neuroscience
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2023.05.002

N-Methyl-D-aspartate ionotropic glutamate receptors (NMDARs) play key roles in synaptogenesis, synaptic maturation, long-term plasticity, neuronal network activity, and cognition. Mirroring this wide range of instrumental functions, abnormalities in NMDAR-mediated signaling have been associated with numerous neurological and psychiatric disorders. Thus, identifying the molecular mechanisms underpinning the physiological and pathological contributions of NMDAR has been a major area of investigation. Over the past decades, a large body of literature has flourished, revealing that the physiology of ionotropic glutamate receptors cannot be restricted to fluxing ions, and involves additional facets controlling synaptic transmissions in health and disease. Here, we review newly discovered dimensions of postsynaptic NMDAR signaling supporting neural plasticity and cognition, such as the nanoscale organization of NMDAR complexes, their activity-dependent redistributions, and non-ionotropic signaling capacities. We also discuss how dysregulations of these processes may directly contribute to NMDAR-dysfunction-related brain diseases. Dupuis et al. discuss recent advances in our understanding of the glutamatergic NMDA receptor, focusing mainly on the dynamics and nanoscale organization of membrane NMDA receptors and their emerging role in ionotropic and non-ionotropic signaling.