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.
Schwann cells (SCs) are known to play an important role for the regeneration of mammalian peripheral nerves. Their effect is likely due to the production of neuronotrophic and/or supportive factors. Here we study the effect of intraocular transplant of SCs on the survival of rat retinal ganglion cells (RGCs) after the intracranial section of the optic nerve. SCs were injected intraocularly in adult hooded rats. Surviving RGCs were retrogradely labeled with horseradish peroxidase applied to the proximal stump of the optic nerve. Results show that intraocular transplants of SCs promote the survival of a large number ofRGCs for periods as long as 9 and 14 weeks after optic nerve section. In experimental retinae, surviving RGCs were 2-to 8-fold more numerous than in controls. This finding suggests that SCs are the source of factors that promote the survival ofRGCs. Nerve growth factor is produced by SCs, and the intraocular injection of nerve growth factor has been previously shown to promote RGC survival. The rescuing effect of SCs on RGCs is greater than that obtained by intraocular injection of nerve growth factor. This greater effect may be due to the action of other neurotrophic factors produced by SCs or by transplanted SCs producing NGF in a sustained fashion.The limited capacity of central nervous system (CNS) neurons to regenerate is thought to be due in part to the presence of nonpermissive factors such as myelin-producing oligodendrocytes (1) or to the absence of neurotrophic factors, or to both (2). In the peripheral nervous system, where regeneration takes place, Schwann cells (SCs) play an important role in promoting regeneration (3). To some extent they also can promote regeneration of CNS neurons. A peripheral nerve segment grafted to the optic nerve promotes partial survival and regeneration of rat retinal ganglion cells (RGCs) (4). This effect is supposed to be due to nonneuronal cells, presumably SCs, present in the graft (4, 5). The positive effect of SCs on regeneration and survival of injured neurons is believed to be due to the production of supportive or neuronotrophic molecules, or both. For instance, there is evidence indicating that SCs produce nerve growth factor (NGF) or a NGF-like protein in vitro (6) and after peripheral nerve injury in vivo (7,8). Recently, it has been shown that repetitive intraocular injections of NGF enhance the survival of axotomized rat RGCs (9). In the present study we test the hypothesis that intraocular transplant of SCs promotes the survival of rat RGCs after axotomy.Our results show that SCs are dramatically effective in rescuing RGCs from degeneration. Whereas in control retinae only 5% of the total population of RGCs survive 9 weeks after optic nerve section, in experimental retinae survival of RGCs was enhanced 2-to 8-fold. In experimental retinae RGCs also display a normal soma size. Hamilton syringe. The tip of the needle was inserted under microscopic guidance through the dorsal limbus of the eye. The injection was performed several days before...
Using light microscopic immunocytochemistry, we have studied the distribution of protein gene product 9.5 (PGP 9.5), a neuron-specific protein first extracted from human brain (Doran et al., '83:J. Neurochem. 40:1542-1547), in the vertebrate retina. Retinas were obtained from frog, chicken, rat, rabbit, cow, cat, dog, and human. No immunoreactivity was observed in frog and only a faint staining was present in chicken. In mammalian retinas, a strong positive reaction was restricted to horizontal and ganglion cells, with minor interspecies variations. Immunostaining was present throughout the cell body and the dendritic tree in horizontal cells. At the level of retinal ganglion cells, immunolabel was particularly abundant in cell bodies and axons forming the optic nerve. Only the main dendrites were stained, the remainder of the dendritic tree giving rise to a diffuse punctate reaction in the inner plexiform layer. In rats, displaced amacrine cells, which are known to contribute largely (40-50%) to the total neuronal population within the ganglion cell layer (Perry, '81: Neuroscience 6:931-944) were not immunoreactive, as demonstrated from (i) analysis of the morphology, cell size and cell density of immunoreactive neurons in wholemounts; (ii) colocalization of retrograde label and PGP 9.5 immunoreactivity in about 80% of ganglion cells after injection of peroxidase into the optic nerve; and (iii) reduction of immunoreactivity in the inner plexiform and ganglion cell layers following optic nerve transection. Western blot analysis of extracts from rabbit retinas indicated that the immunoreactive species is PGP 9.5 or a closely related molecule. Recent studies have demonstrated that PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase (Wilkinson et al., '89:Science 246:670-673). The present results, therefore, suggest that differences in the ubiquitination process exist between retinal neurons.
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