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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.

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.

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.

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

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

(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)

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.

The process by which an inwardly transported molecule leads to the efflux of a different molecule by the same transporter.

A gene that contains an elevated number of CAG trinucleotide repeats in Huntington's disease and is the disease-causing agent.

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.

A mitochondrial toxin that inhibits succinate dehydrogenase (part of complex II).

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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