A behavioral model of excitotoxicity: retinal degeneration, loss of vision, and subsequent recovery after intraocular NMDA administration in adult rats.
To establish a new behavioral animal model of excitotoxicity, we injected adult rats intraocularly with a single dose of 2, 20, or 100 nmol of N-methyl-D-aspartate (NMDA). We quantified visual impairment by plotting the size of the visual field in which the rats successfully oriented towards a small, moving target. In comparison to the saline-injected (contralateral) control side, the side injected with 2 nmol of NMDA was not significantly impaired. When injected with higher doses, the rats were nearly blind immediately after surgery, with only about 20% (20 nmol NMDA) or 10% (100 nmol NMDA) of residual vision. Within about 3 weeks, however, visual performance returned to near-normal levels. Simultaneous intraocular administration of a non-competitive NMDA-antagonist, MK-801 (1 nmol), resulted in complete behavioral protection. NMDA administration led to a dose-dependent loss of cells within the ganglion cell layer, as assessed in whole-mounted retinae which were retrogradely labelled with horseradish peroxidase (HRP). Whereas 2 nmol of NMDA led to the loss of about 30% of retinal ganglion cells (RGCs), at higher NMDA doses only 13% of the RGCs survived. After the injection of 20 nmol of NMDA, large-diameter RGCs (> 22 microns) survived the lesion to a greater extent than small diameter cells (8-21 microns); at 100 nmol cells of all diameters were equally affected. The number of Nissl-stained cells with small diameters (< 11 microns), presumed to be displaced amacrine cells, was also affected by NMDA, although to a lesser degree. Analysis of behavioral performance (vision score) and the number of cells in the retina revealed a correlation of r = 0.76 between visual performance and the number of HRP-filled RGCs immediately after surgery. Lower correlations were found between visual performance and cells stained with Nissl of diameters smaller than 11 microns (presumed RGCs without retinofugal connections; r = 0.55 and r = 0.58, respectively). Because of the spontaneous recovery of vision, all correlations declined to values near 0 after 3 weeks. Thus, despite a dramatic loss of RGCs following NMDA administration, visual deficits recover significantly in adult rats within 2-3 weeks.
Sabel
B A
BA
Institute of Medical Psychology, Otto-von-Guericke University of Magdeburg Medical School, Germany.
Sautter
J
J
Stoehr
T
T
Siliprandi
R
R
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005123:Eye; D006735:Horseradish Peroxidase; D007267:Injections; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009949:Orientation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012162:Retinal Degeneration / Q000139:chemically induced / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000187:drug effects; D014786:Vision Disorders / Q000139:chemically induced / Q000473:pathology*; D014794:Visual Fields / Q000187:drug effects / Q000502:physiology
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D006735:Horseradish Peroxidase