Type-specific stabilization and target-dependent survival of regenerating ganglion cells in the retina of adult rats

Abstract

Axotomy-induced degradation of retinal ganglion cells (RGC) can be delayed if the destructive features of activated microglial cells are pharmacologically neutralized, and prevented if the axons are permitted to regrow into transplanted autologous peripheral nerve (PN) pieces. This study was undertaken to classify the regenerating rat RGC and to examine target-dependent effects on survival of subsets of neurons. In analogy to the normal rat retina, we have categorized the retrogradely labeled, regenerating RGC into five classes which are morphologically distinct and reminiscent of normal RGC correlates (types I, II, III, delta-cells, and displaced RGC). Six weeks after transplantation of peripheral nerve to the transected optic nerve, large, type I-like cells (RI) constituted 5.7 +/- 2.0% of the total population. Smaller, round to oval cells of type RII represented the majority of labeled neurons (64.5 +/- 6.1%). Cells of type RIII constituted 4.6 +/- 1.7% of the total population and had very typical, middlesized, polarized perikarya and large dendrites. Less frequent (< 1%) were R-delta and displaced RGC. Transplantation of a PN graft which was not reconnected with a central target (blind-ending group) and monitoring of the extant neurons showed a progressive disappearance of the regenerating RGC, such that 6 months after surgery predominantly few large cells survived. When the retinas were treated with macrophage/microglia- inhibiting factor (MIF), and the regenerating axons were guided into the pretectum, predominantly large RGC of type RI survived. Guidance of the axons into their major natural target, the superior colliculus (SC), resulted in selective survival of many small, RII-like RGC. Calculation of the dendritic coverage factors for the major types of RGC revealed that dendrites of the most abundant small cells of type RII overlapped uniformly and covered the retinal surface completely, whereas cells of types RI and RIII did not suffice for surface coverage. The results suggest that combined suppression of axotomy- induced microglial activation and guidance of regenerating axons with a PN graft into central targets is a suitable technique to produce sufficient numbers of regenerating axons which may retrieve some functional properties. Target-specific neuronal contacts are likely involved in morphological stabilization and better survival of regenerating neurons.

Voltage-Activated Calcium Currents in Rat Retinal Ganglion CellsIn Situ: Changes during Prenatal and Postnatal Development

“…Only large diameter ganglion cells were selected. Because ␣-or type I RGC s have been shown to have much larger cell somata than displaced amacrine cells and other types of RGC s (Perry, 1979;Thanos and Mey, 1995), we assume that we mainly recorded from this ganglion cell type. Other morphological criteria were inapplicable, because dendritic arborization, on which ganglion cell identification in adults is normally based, is immature in embryonic and postnatal stages ϽP10.…”

Anti-semaphorin 3A Antibodies Rescue Retinal Ganglion Cells from Cell Death following Optic Nerve Axotomy

“…Indeed, partial and temporal rescue of RGC from axotomy-induced apoptosis was obtained by several approaches. These included early treatment with microglial inhibitors (36,37), glial or brain-derived neurotrophic factors (38,39), caspase inhibitors (40,41), implantation of stimulated macrophages (42), and overexpression of Bcl-2 (43,44). Therefore, we chose the visual system as an in vivo model in which neuronal apoptosis can be induced and, more importantly, that can also offer an opportunity to intervene and alter the fate of the injured RGC.…”

Axons of alpha ganglion cells regenerate faster than other types into a peripheral nerve graft in adult cats

“…Although we have not examined systematically the number of regenerated RGCs over 8 weeks, the numbers fell to 1,000 -1,500 in 20 weeks after transplantation (Watanabe and Fukuda, 2002). Similarly, Thanos and Mey (1995) reported in rats that the number of regenerated RGCs decrease slowly from 6 weeks after transplantation. From these reports, it is plausible that RGCs regenerating axons into a blind-ended graft may degenerate gradually after 6 or 8 weeks.…”