Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders

G. E. Hardingham, H. Bading

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)682-696
Number of pages15
JournalNature Reviews Neuroscience
Issue number10
Publication statusPublished - Oct 2010


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