Invulnerability of retinal ganglion cells to NMDA excitotoxicity

Mol Cell Neurosci. 2004 Aug;26(4):544-57. doi: 10.1016/j.mcn.2004.05.002.


NMDA excitotoxicity has been proposed to mediate the death of retinal ganglion cells (RGCs) in glaucoma and ischemia. Here, we reexamine the effects of glutamate and NMDA on rat RGCs in vitro and in situ. We show that highly purified RGCs express NR1 and NR2 receptor subunits by Western blotting and immunostaining, and functional NMDA receptor channels by whole-cell patch-clamp recording. Nevertheless, high concentrations of glutamate or NMDA failed to induce the death of purified RGCs, even after prolonged exposure for 24 h. RGCs co-cultured together with ephrins, astrocytes, or mixed retinal cells were similarly invulnerable to glutamate and NMDA, though their NMDA currents were 4-fold larger. In contrast, even a short exposure to glutamate or NMDA induced the rapid and profound excitotoxic death of most hippocampal neurons in culture. To determine whether RGCs in an intact retina are vulnerable to excitotoxicity, we retrogradely labeled RGCs in vivo using fluorogold and exposed acutely isolated intact retinas to high concentrations of glutamate or NMDA. This produced a substantial and rapid loss of amacrine cells; however, RGCs were not affected. Nonetheless, RGCs expressed NMDA currents in situ that were larger than those reported for amacrine cells. Interestingly, the NMDA receptors expressed by RGCs were extrasynaptically localized both in vitro and in situ. These results indicate that RGCs in vitro and in situ are relatively invulnerable to glutamate and NMDA excitotoxicity compared to amacrine cells, and indicate that important, as yet unidentified, determinants downstream of NMDA receptors control vulnerability to excitotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amacrine Cells / cytology
  • Amacrine Cells / drug effects
  • Amacrine Cells / metabolism
  • Animals
  • Animals, Newborn
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Resistance / physiology
  • Fluorescent Dyes
  • Glutamic Acid / metabolism*
  • Glutamic Acid / toxicity
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • N-Methylaspartate / toxicity*
  • Neurotoxins / metabolism*
  • Neurotoxins / toxicity
  • Rats
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Retinal Degeneration / chemically induced
  • Retinal Degeneration / metabolism*
  • Retinal Degeneration / physiopathology
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / drug effects
  • Retinal Ganglion Cells / metabolism*
  • Stilbamidines
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology


  • 2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt
  • Fluorescent Dyes
  • NR1 NMDA receptor
  • NR2A NMDA receptor
  • Neurotoxins
  • Receptors, N-Methyl-D-Aspartate
  • Stilbamidines
  • Glutamic Acid
  • N-Methylaspartate