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NMDA receptor-mediated excitotoxicity depends on the coactivation of synaptic and extrasynaptic receptors

X Zhou1, D Hollern, J Liao

  • 1Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.

Cell Death & Disease
|March 30, 2013
PubMed

Insights

N-methyl-D-aspartate receptor (NMDAR) overactivation can harm neurons. This study shows that activating N-methyl-D-aspartate receptors (NMDAR) alone doesn't cause cell death, but coactivation leads to neurodegeneration.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • N-methyl-D-aspartate receptors (NMDAR) overactivation is implicated in neurodegeneration.
  • The prevailing theory posits that synaptic and extrasynaptic NMDAR have opposing effects on cell fate, with extrasynaptic NMDAR mediating cell death.

Purpose of the Study:

  • To investigate the bidirectional regulation of cell fate by NMDAR activation.
  • To clarify the roles of synaptic and extrasynaptic NMDAR in neuronal survival and death pathways.
  • To re-evaluate the prevailing theory on NMDAR-mediated neurodegeneration.

Main Methods:

  • NMDA stimulation at varying doses to differentially activate synaptic and extrasynaptic NMDAR.
  • Assessment of pro-survival and pro-death signaling pathways.
  • Treatment with memantine, a known NMDAR antagonist.
  • Long-term and short-term exposure to high-dose NMDA and oxygen-glucose deprivation.
  • Genome-wide transcriptional analysis.

Main Results:

  • Low-dose NMDA activated synaptic NMDAR, promoting pro-survival signaling.
  • Higher doses activated both synaptic and extrasynaptic NMDAR, leading to cell death.
  • Activation of either synaptic or extrasynaptic NMDAR alone did not induce cell death or pro-death signaling.
  • Memantine inhibited signaling through both synaptic and extrasynaptic NMDAR, reducing NMDA-induced cell death.
  • Prolonged NMDA exposure or oxygen-glucose deprivation triggered cell death and suppressed pro-survival signaling.
  • Transcriptional responses to synaptic and extrasynaptic NMDAR activation were largely overlapping, not counteracting.

Conclusions:

  • NMDAR activation bidirectionally regulates cell fate via pro-survival and pro-death signaling.
  • Neither synaptic nor extrasynaptic NMDAR activation alone is neurotoxic.
  • Neurotoxicity arises from the magnitude and duration of coactivation of both synaptic and extrasynaptic NMDAR.
  • The prevailing theory on counteracting effects of synaptic and extrasynaptic NMDAR is limited.

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