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

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.