Regenerative glutamate release by presynaptic NMDA receptors contributes to spreading depression

J Cereb Blood Flow Metab. 2013 Oct;33(10):1582-94. doi: 10.1038/jcbfm.2013.113. Epub 2013 Jul 3.


Spreading depression (SD) is a slowly propagating neuronal depolarization that underlies certain neurologic conditions. The wave-like pattern of its propagation suggests that SD arises from an unusual form of neuronal communication. We used enzyme-based glutamate electrodes to show that during SD induced by transiently raising extracellular K(+) concentrations ([K(+)]o) in rat brain slices, there was a rapid increase in the extracellular glutamate concentration that required vesicular exocytosis but unlike fast synaptic transmission, still occurred when voltage-gated sodium and calcium channels (VGSC and VGCC) were blocked. Instead, presynaptic N-methyl-D-aspartate (NMDA) receptors (NMDARs) were activated during SD and could generate substantial glutamate release to support regenerative glutamate release and propagating waves when VGSCs and VGCCs were blocked. In calcium-free solutions, high [K(+)]o still triggered SD-like waves and glutamate efflux. Under such a condition, glutamate release was blocked by mitochondrial Na(+)/Ca(2+) exchanger inhibitors that likely blocked calcium release from mitochondria secondary to NMDA-induced Na(+) influx. Therefore presynaptic NMDA receptor activation is sufficient for triggering vesicular glutamate release during SD via both calcium entry and release from mitochondria by mitochondrial Na(+)/Ca(2+) exchanger. Our observations suggest that presynaptic NMDARs contribute to a cycle of glutamate-induced glutamate release that mediate high [K(+)]o-triggered SD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biosensing Techniques
  • Brain / metabolism*
  • Brain / physiopathology
  • Calcium / metabolism
  • Cortical Spreading Depression / physiology*
  • Electrodes
  • Electrophysiology
  • Female
  • Glutamic Acid / metabolism*
  • In Vitro Techniques
  • Male
  • Potassium / administration & dosage
  • Potassium / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Receptors, Presynaptic / metabolism*
  • Sodium-Calcium Exchanger / metabolism
  • Synaptic Transmission / physiology


  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Presynaptic
  • Sodium-Calcium Exchanger
  • Glutamic Acid
  • Potassium
  • Calcium