Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders

By G. Hardingham, Hilmar Bading. Nature Reviews Neuroscience, 2010

1,630 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f216ad2c7e3c068657818711018db8b21324d300

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. K. Ressler
2. Stephane Oliet
3. M. Popoli
4. G. Sanacora
5. G. Treccani

In Molecular Biology

1. D. Bailey
2. Maria Luisa Fiorello
3. J. Cobley

Citations in the corpus

• Excitotoxicity: bridge to various triggers in neurodegenerative disorders. (2013, background): “Immunohistochemically, synaptic N-methylD-aspartate receptors (NMDARs) are classically defined as functional receptors that are activated by glutamate released during low-frequency synaptic events (Kalia et al., 2008; Hardingham and Bading, 2010).”
• Towards a glutamate hypothesis of depression (2011, background): “…suggesting that increased activation of extrasynaptic relative to synaptic glutamate receptors results in cellular toxicity and neurodegeneration (Hardingham and Bading, 2010), it is possible that reduced extracellular glutamate clearance, especially in the face of excessive glutamate release,…”
• Regulation of extrasynaptic signaling by polysialylated NCAM: Impact for synaptic plasticity and cognitive functions (2017, background): “perisynaptic, if they lie within 100 nm from the PSD (Hardingham and Bading, 2010; Petralia et al., 2010).”
• Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. (2012, background): “Thereby, NMDARs are crucial players in both physiological and pathophysiological processes, and as such, they have been studied extensively, generating massive clinical interest as potential therapeutic targets (Hardingham and Bading, 2010; Tsai et al., 2004).”
• Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017, background): “Augmented release of glutamate from astrocytes has been shown to be decrease brain-derived neurotrophic factor and increase excitotoxicity (Hardingham and Bading, 2010).”
• Role of glutamate and NMDA receptors in Alzheimer’s disease (2016, neutral): “In AD, extrasynaptic NMDAR-mediated signaling pathway antagonizes the cell survival pathway mediated through synaptic NMDARs by inactivating CREB and activating FOXO transcription factors and promoting the related pro-death and oxidative stress signaling [20, 21].”
• 13 reasons why the brain is susceptible to oxidative stress (2018, background): “signalling—for example, leading to sustained calpain signalling [74].”