The present study provides evidence that the adult mammalian retina is highly sensitive to the excitotoxic action of NMDA. In particular, we have investigated the effects of a single intravitreal injection of different doses of N-methyl-D-aspartate (NMDA) (2–200 nmoles) on the adult rat retina. Morphological evaluation of transverse sections of retinae demonstrated a dose-dependent loss of cells in the ganglion cell layer (GCL) and a reduction in the thickness of the inner plexiform layer. No obvious alterations were noted in the more distal retinal layers. Quantitative analyses of Nissl-stained whole-mounted retinae revealed that administration of 20 nmoles of NMDA resulted in a 70% loss of cells with a soma diameter greater than 8 μm (presumed retinal ganglion cells); a 20% loss of cells with a soma diameter smaller than 8 μm (presumed displaced amacrine cells) was also observed. In addition, NMDA produced a dose-dependent decrease of retinal choline acetyltransferase (ChAT) activity, suggesting that NMDA affects cholinergic amacrine cells as well. MK-801, a non-competitive NMDA antagonist, completely prevented the NMDA-induced loss of cells in the GCL and blocked, in a dose-dependent manner, the NMDA-induced decrease of ChAT activity. The excitotoxic action of NMDA observed in these experiments is thus likely mediated through the NMDA receptor subtype. This ”in vivo” model may be utilized to identify potential drugs that antagonize or limit the deleterious effects consequent to NMDA receptor overstimulation in the central nervous system.
The ability of NGF (2.5S subunit) to support the survival of adult rat retinal ganglion cells (RGCs) and optic nerve fibers after intracranial section of the optic nerve was investigated. NGF was injected intraocularly at a dose of 3 micrograms/injection every 2.3 d from the day of axotomy to analysis. Control animals received cytochrome c injections. The survival of RGCs was analyzed in whole-mounted retinas after either cresyl violet staining or labeling with HRP applied to the proximal stump of the optic nerve. Survival times were 5 and 7 weeks. Diameter distribution and number of myelinated optic nerve fibers were assessed in ultrathin cross sections of the optic nerve. We found that RGCs surviving axotomy were much more numerous following NGF treatment compared with controls. Large-size cells were, in particular, preserved by NGF treatment. The quantitative ultrastructural studies indicated that the number of myelinated optic nerve fibers at 5 and 7 weeks postaxotomy was significantly greater in the NGF group with respect to the cytochrome c group. In agreement with the results obtained at the level of the RGCs, large-diameter axons were, in particular, preserved. We conclude that NGF injected intraocularly is effective in promoting the survival of RGCs and optic nerve fibers at least for a period as long as 7 weeks after intracranial section of the optic nerve.
SUMMARY1. The effect of intraventricular administration of nerve growth factor (NGF) by means of a cannula-minipump system was studied in kittens monocularly deprived during the critical period. The ocular dominance of area 17 neurones of NGF-treated and control kittens was determined by conventional extracellular recordings. The soma size of cells in A and Al laminae of the lateral geniculate nucleus (LGN) was also evaluated in Cresyl Violet preparations.2. Binocularly responsive neurones were found to be significantly more numerous in NGF-treated than in control kittens. The shrinkage of cells from the deprived LGN laminae normally observed in control kittens was prevented by NGF administration.3. Following an initial period of monocular deprivation (MD) kittens subsequently treated with NGF showed a substantial recovery of functional binocular connections.4. These findings indicate that the administration of NGF during the period of deprivation reduces the amblyopic effects of MD, while its administration to kittens with both eyes open following the initial deprivation promotes recovery of the deprived eye.5. Neurotrophic factors may contribute to the regulation of experience-dependent modifications of synaptic connectivity in the visual cortex.
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