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KEY POINTS * NMDARs (_N_-methyl-D-aspartate receptors) have long been known for their role in neuropathology, and inappropriate activity is implicated in neuronal loss in acute disorders

such as stroke and traumatic brain injury. Certain chronic neurodegenerative diseases are also associated with abnormal NMDAR activity, including Huntington's and Alzheimer's

diseases. However, the destructive effects of NMDAR activity are in striking contrast to the observation that the survival and resistance to trauma of several neuronal types is boosted by

physiological synaptic NMDAR activity and function. Thus, there is a dichotomy of NMDAR signalling. * Recent studies have shown that cellular responses to NMDAR activation can depend on the

receptor location. Activation of synaptic NMDARs, particularly when activated trans-synaptically, promotes neuronal health, whereas chronic activation of extrasynaptic NMDARs couples to cell

death pathways. Differences are observed even when the overall Ca2+ loads triggered via the two routes are similar. * Synaptic NMDAR activity strongly promotes neuronal health by initiating

a programme of transcriptional changes that promote resistance to various traumatic stimuli. Synaptic NMDARs control a nuclear Ca2+-regulated multi-gene program that protects against

excitotoxic and apoptotic insults. Transcriptional suppression of key components of the intrinsic apoptosis pathway also restricts the apoptotic potential of neurons. Moreover, synaptic

NMDAR activity promotes resistance to oxidative insults by boosting intrinsic antioxidant defences through transcriptional changes of proteins encoding antioxidant genes and regulatory

factors. * Extrasynaptic NMDAR activity is coupled to several signalling pathways that promote neuronal death or vulnerability to trauma. These include the dephosphorylation and inactivation

of the pro-survival transcription factor cyclic-AMP response element binding protein (CREB), nuclear import of the pro-death transcription factor forkhead box protein O (FOXO), inactivation

of extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein (MAP) kinase, and calpain-dependent striatal enriched tyrosine phosphatase (STEP) cleavage and activation of

p38 MAP kinase. * A shift in the balance from synaptic towards extrasynaptic NMDAR signalling may be an important factor in the aetiology of neurodegenerative diseases. In Huntington's

disease, mutant huntingtin causes a specific increase in extrasynaptic NMDAR currents. Furthermore, extrasynaptic NMDAR activity in turn promotes the toxicity of mutant huntingtin and

synaptic NMDAR activity reduces mutant huntingtin toxicity by promoting the formation of non-toxic inclusions. In acute ischaemic trauma, cell death may be caused in part by an upregulation

and activation of extrasynaptic NMDARs * In treating disorders associated with abnormal NMDAR activity, therapies aimed at selectively blocking chronic extrasynaptic NMDAR activity without

interfering with normal synaptic NMDAR activity may be better tolerated and more efficacious than conventional antagonists. The NMDAR antagonist memantine is well suited to this role, which

may explain its tolerance in humans and its recently demonstrated efficacy in preclinical models of Huntington's disease. ABSTRACT There is a long-standing paradox that NMDA

(_N_-methyl-D-aspartate) receptors (NMDARs) can both promote neuronal health and kill neurons. Recent studies show that NMDAR-induced responses depend on the receptor location: stimulation

of synaptic NMDARs, acting primarily through nuclear Ca2+ signalling, leads to the build-up of a neuroprotective 'shield', whereas stimulation of extrasynaptic NMDARs promotes cell

death. These differences result from the activation of distinct genomic programmes and from opposing actions on intracellular signalling pathways. Perturbations in the balance between

synaptic and extrasynaptic NMDAR activity contribute to neuronal dysfunction in acute ischaemia and Huntington's disease, and could be a common theme in the aetiology of

neurodegenerative diseases. Neuroprotective therapies should aim to both enhance the effect of synaptic activity and disrupt extrasynaptic NMDAR-dependent death signalling. Access through

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CONTENT BEING VIEWED BY OTHERS NON-CANONICAL INTERPLAY BETWEEN GLUTAMATERGIC NMDA AND DOPAMINE RECEPTORS SHAPES SYNAPTOGENESIS Article Open access 02 January 2024 MOLECULAR MECHANISMS OF

EXCITOTOXICITY AND THEIR RELEVANCE TO THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES—AN UPDATE Article Open access 19 May 2025 ENHANCING GLUN2A-TYPE NMDA RECEPTORS IMPAIRS LONG-TERM SYNAPTIC

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Bell and C. P. Bengston for comments on the manuscript, and R. Petralia for supplying the electronmicrographs in Box 1. Work in the authors' laboratories is supported by the Wellcome

Trust, the Medical Research Council (MRC), the Biotechnology and Biological Sciences Research Council, the Royal Society (G.E.H.) and by the Alexander von Humboldt Foundation, the European

Research Council Advanced Grant, the Deutsche Forschungsgemeinschaft, the EU Network of Excellence NeuroNE and the EU Project Glutamate Receptor Interacting Proteins as Novel Neuroprotective

Targets (GRIPANNT) (H.B.). G.E.H. is an MRC senior non-clinical research fellow. H.B. is a member of the Excellence Cluster _CellNetworks_ at Heidelberg University. AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS * Centre for Integrative Physiology, University of Edinburgh, School of Biomedical Sciences, Hugh Robson Building, EH8 9XD, Edinburgh, UK Giles E. Hardingham *

Department of Neurobiology, Interdisciplinary Center for Neurosciences (IZN), Im Neuenheimer Feld 364, D69120, Heidelberg, Germany Hilmar Bading * Hilmar Bading Authors * Giles E. Hardingham

View author publications You can also search for this author inPubMed Google Scholar * Hilmar Bading View author publications You can also search for this author inPubMed Google Scholar

ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED LINKS RELATED LINKS FURTHER INFORMATION Giles E. Hardingham's homepage Hilmar

Bading's homepage GLOSSARY * Pro-apoptotic Bcl2 homology domain 3 (BH3)-only member gene (Also known as _Puma_.) A gene encoding a pro-apoptotic member of the Bcl2 family that contains

only a BH3 domain, as opposed to those that contain multiple BH domains (for example, _Bax_ and _Bak_) * Calpain A family of Ca2+-dependent cysteine proteases. * Reversed uptake Describes

the action of glutamate transporters in pumping glutamate out of the cell, as opposed to their usual function of taking glutamate up from the extracellular space. Ischaemic conditions cause

reversed uptake owing to membrane depolarization. * Hetero-exchange The process by which an inwardly transported molecule leads to the efflux of a different molecule by the same transporter.

* Huntingtin A gene that contains an elevated number of CAG trinucleotide repeats in Huntington's disease and is the disease-causing agent. * Sumoylation The process of covalent

attachment of small ubiquitin-like modifier (SUMO) protein onto another protein. This modification typically alters the activity, stability or localization of the modified protein. *

3-nitropropanoic acid A mitochondrial toxin that inhibits succinate dehydrogenase (part of complex II). * Transactivating capacity The ability of a transcription factor or co-activator to

enhance gene transcription when associated with that gene's promoter. This may be influenced by post-translational modifications that determine the association of accessory factors,

including chromatin-modifying enzymes. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hardingham, G., Bading, H. Synaptic versus extrasynaptic NMDA

receptor signalling: implications for neurodegenerative disorders. _Nat Rev Neurosci_ 11, 682–696 (2010). https://doi.org/10.1038/nrn2911 Download citation * Published: 15 September 2010 *

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