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  • Review Article
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Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders

Nature Reviews Neuroscience volume 11, pages 682–696 (2010)Cite this article

Subjects

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.

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Figure 1: χ-shaped model of NMDAR-dependent excitotoxicity.
Figure 2: Neuroprotective pathways activated by synaptic NMDAR activity.
Figure 3: Opposing effects of synaptic and extrasynaptic NMDAR signalling on gene expression.
Figure 4: Synaptic NMDAR-dependent transcriptional changes have both anti-apoptotic and antioxidant effects.
Figure 5: Activators and effectors of extrasynaptic NMDAR activity.
Figure 6: Clinical relevance of the balance between synaptic and extrasynaptic NMDAR activity.

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Acknowledgements

We thank K. 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.

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  1. Centre for Integrative Physiology, University of Edinburgh, School of Biomedical Sciences, Hugh Robson Building, EH8 9XD, Edinburgh, UK

    Giles E. Hardingham

  2. Department of Neurobiology, Interdisciplinary Center for Neurosciences (IZN), Im Neuenheimer Feld 364, D69120, Heidelberg, Germany

    Hilmar Bading

  3. Hilmar Bading

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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.

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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

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