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Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways

G E Hardingham1, Y Fukunaga, H Bading

  • 1MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.

Nature Neuroscience
|April 16, 2002
PubMed

Insights

Synaptic NMDA receptors promote neuron survival by activating CREB, while extrasynaptic NMDA receptors trigger cell death. Blocking extrasynaptic receptors may prevent neurodegeneration in conditions like stroke.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • NMDA receptors are crucial for synaptic plasticity and neuronal function.
  • Both synaptic and extrasynaptic NMDA receptors mediate calcium influx, but their downstream effects are not fully understood.
  • Dysregulation of NMDA receptor activity is implicated in various neuropathological conditions.

Purpose of the Study:

  • To investigate the differential roles of synaptic and extrasynaptic NMDA receptors in regulating CREB (cAMP response element binding protein) function.
  • To determine the impact of these receptors on gene expression, neuron survival, and cell death pathways.
  • To explore the therapeutic potential of targeting specific NMDA receptor populations.

Main Methods:

  • Electrophysiology to study calcium influx through synaptic and extrasynaptic NMDA receptors.
  • Biochemical assays to assess CREB phosphorylation and activity.
  • Gene expression analysis to quantify BDNF (brain-derived neurotrophic factor) levels.
  • Mitochondrial membrane potential assays and cell viability assays to evaluate neuronal survival and apoptosis.

Main Results:

  • Calcium entry via synaptic NMDA receptors stimulated CREB activity and BDNF gene expression, similar to L-type calcium channels.
  • Calcium entry via extrasynaptic NMDA receptors activated a CREB shut-off pathway, inhibiting BDNF expression.
  • Synaptic NMDA receptor activation conferred anti-apoptotic effects.
  • Extrasynaptic NMDA receptor activation led to loss of mitochondrial membrane potential and cell death, particularly under excitotoxic conditions.

Conclusions:

  • Synaptic and extrasynaptic NMDA receptors exert opposing effects on CREB-mediated gene expression and neuronal fate.
  • Extrasynaptic NMDA receptors play a detrimental role in excitotoxicity and neuronal damage.
  • Targeting extrasynaptic NMDA receptors offers a potential strategy to protect neurons in stroke and other glutamate-related neuropathologies.

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