A BEHAVIORAL-MODEL OF EXCITOTOXICITY - RETINAL DEGENERATION, LOSS OF VISION, AND SUBSEQUENT RECOVERY AFTER INTRAOCULAR NMDA ADMINISTRATION IN ADULT-RATS
Ba. Sabel et al., A BEHAVIORAL-MODEL OF EXCITOTOXICITY - RETINAL DEGENERATION, LOSS OF VISION, AND SUBSEQUENT RECOVERY AFTER INTRAOCULAR NMDA ADMINISTRATION IN ADULT-RATS, Experimental Brain Research, 106(1), 1995, pp. 93-105
To establish a new behavioral animal model of excitotoxicity, we injec
ted adult rats intraocularly with a single dose of 2, 20, or 100 nmol
of N-methyl-D-aspartate (NMDA). We quantified visual impairment by plo
t ting the size of the visual field in which the rats successfully ori
ented towards a small, moving target. In comparison to the saline-inje
cted (contralateral) control side, the side injected with 2 nmol of NM
DA was not significantly impaired. When injected with higher doses, th
e rats were nearly blind immediately after surgery, with only about 20
% (20 nmol NMDA) or 10% (100 nmol NMDA) of residual vision. Within abo
ut 3 weeks, however, visual performance returned to near-normal levels
. Simultaneous intraocular administration of a non-competitive NMDA-an
tagonist, 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 r
etrogradely 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 inject
ion of 20 nmol of NMDA, large-diameter RGCs (>22 mu m) survived the le
sion to a greater extent than small diameter cells (8-21 mu m); at 100
nmol cells of all diameters were equally affected. The number of Niss
l-stained cells with small diameters (<11 mu m), presumed to be displa
ced amacrine cells, was also affected by NMDA, although to a lesser de
gree. Analysis of behavioral performance (vision score) and the number
of cells in the retina revealed a correlation of r=0.76 between visua
l performance and the number of HRP-filled RGCs immediately after surg
ery. Lower correlations were found between Visual performance and cell
s stained with Nissl of diameters smaller than 11 mu m (presumably dis
placed amacrine cells) or larger than 11 mu m (presumed RGCs without r
etinofugal connections; r=0.55 and r=0.58, respectively). Because of t
he 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 r
ats within 2-3 weeks.