Development of Single Retinofugal Axon Arbors in Normal and β2 Knock-Out Mice

Abstract

The maturation of retinal ganglion cell (RGC) axon projections in the dorsal lateral geniculate nucleus (dLGN) and the superior colliculus (SC) relies on both molecular and activity-dependent mechanisms. Despite the increasing popularity of the mouse as a mammalian visual system model, little is known in this species about the normal development of individual RGC axon arbors or the role of activity in this process. We used a novel in vivo single RGC labeling technique to quantitatively characterize the elaboration and refinement of RGC axon arbors in the dLGN and SC in wild-type (WT) and ␤2-nicotinic acetylcholine receptors mutant (␤2 Ϫ/Ϫ ) mice, which have perturbed retinal waves, during the developmental period when eye-specific lamination and retinotopic refinement occurs. Our results suggest that eye-specific segregation and retinotopic refinement in WT mice are not the result of refinement of richly exuberant arbors but rather the elaboration of arbors prepositioned in the proper location combined with the elimination of inappropriately targeted sparse branches. We found that retinocollicular arbors mature ϳ1 week earlier than retinogeniculate arbors, although RGC axons reach the dLGN and SC at roughly the same age. We also observed striking differences between contralateral and ipsilateral RGC axon arbors in the SC but not in the LGN. These data suggest a strong influence of target specific cues during arbor maturation. In ␤2 Ϫ/Ϫ mice, we found that retinofugal single axon arbors are well ramified but enlarged, particularly in the SC, indicating that activity-dependent visual map development occurs through the refinement of individual RGC arbors.

Retinal waves regulate afferent terminal targeting in the early visual pathway

“…This argument was supported by the fact that TZs in the dLGN were enlarged (12,22). Additionally, work has shown that the morphology of single retinogeniculate axon terminals in mice is initially enlarged when retinal waves are disrupted (11). Interestingly, as shown above, we find that following retinal wave blockade in the enucleated ferret, the total size of the projection is diminished (Figs.…”

“…Surprisingly, despite disruptions in afferent terminal refinement in mouse models of retinal wave blockade (11), geniculate RFs in these animals have been reported to be normal (22). Why is it that when retinal waves are blocked, geniculate RFs are enlarged in adult ferrets (Fig.…”

“…Although a Hebbian- like mechanism is thought to drive retinogeniculate afferent terminal refinement (19,20,41), its disruption alone is unlikely to explain the failure of the retinogeniculate projection to expand in enucleates following the blockade of retinal waves. For example, previous work has supported a role for retinal waves in the pruning and consolidation, not the expansion, of retinogeniculate afferent terminals early in development (11,12). Additionally, monocular enucleation has limited effects on afferent terminal morphology in both cats and primates (42,43), with only afferent terminals from Y RGCs expanding in cats (44).…”

“…It has been well recognized that the high specificity of connections between the retina and the dorsal lateral geniculate nucleus (dLGN) is established through several factors. These include gradients of axon guidance molecules that guide the initial coarse targeting of afferent terminals (3)(4)(5)(6), and spontaneous retinal activity (retinal waves) that drives competitive processes important for the refinement and segregation of afferent terminal branches (2,(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

In vivo imaging of the zebrafish retinotectal map

“…Our work in fish, the work of Ruthazer [277] in Xenopus, and the recent work of Dhande [60] in mice, suggests that selective branching and elimination in retinotopic map formation occurs simultaneously across all species.…”