Development of Retinogeniculate Projections

The dorsal lateral geniculate nucleus of the thalamus (dLGN) is the gateway through which visual information is transmitted from the retina to the cortex; therefore, visual perception relies on the ability of dLGN neurons to faithfully relay the specific features of the visual world that are encoded by the retina. Accordingly, the connections between retinal ganglion cells (RGCs) and dLGN neurons are highly precise and organized. ^, For instance, RGC projections are arranged such that neighboring cells in the retina innervate neighboring cells in the dLGN creating a retinotopic map in the thalamus that is capable of maintaining the spatial features of the visual scene. Furthermore, the resolution of the retinal map is also maintained in the dLGN since at maturity few RGCs converge onto dLGN neurons; consequently, dLGN receptive fields are similar to those of RGCs in their size and structure. Another key feature of retinogeniculate organization, which is important for binocular vision, is that the axons arising from each eye are segregated within the dLGN. As a result, mature dLGN neurons are monocularly driven. ^, Finally, some cell-type-specific organization also exists in the dLGN since different types of dLGN neurons reside in distinct laminae and receive inputs from different subtypes of functionally distinct RGCs.

How does precise retinogeniculate circuitry get established during development? Numerous experiments have demonstrated that many aspects of retinogeniculate connectivity are initially imprecise, and that the immature circuit must subsequently undergo refinement in order to achieve its finely tuned mature form. Much of this refinement occurs before the onset of vision, ^, and it is now well established that this early refinement requires both spontaneous retinal activity and molecular cues that are present over development.

Retinogeniculate projections are refined during development

Anatomical studies have shown that when the axons from the two eyes initially invade the dLGN their arbors are extensively overlapped, ^, and functional studies have demonstrated that these overlapping projections give rise to binocularly innervated dLGN neurons. ^, After this initial connectivity is established there is a specific developmental window during which the axons from each eye segregate into non-overlapping territories. ^, This “eye-specific segregation” results in a pattern of ipsilateral and contralateral projections that is highly stereotyped both in size and placement within the dLGN. Eye-specific inputs also segregate functionally. As RGC axons become restricted to the appropriate region of the dLGN their functional synaptic connections in the inappropriate region are lost, resulting in monocularly driven dLGN neurons. ^, In mouse, electrophysiological recordings have demonstrated that dLGN neurons are initially weakly innervated by 12–30 RGCs which get refined down to 4–6 inputs from each eye as segregation proceeds, and finally to just 1–3 strong inputs from a single eye at maturity. While the convergence of RGC inputs onto individual dLGN neurons gets reduced, the nearest neighbor relationships among RGCs are maintained, and thusly, the retinotopic map is sharpened.

In addition to eye-specific segregation, RGC axons undergo further restriction of their arbors into functionally distinct sublaminae. For example, each major class of ganglion cell consists of two subtypes: cells that are depolarized (ON ganglion cells) or hyperpolarized (OFF ganglion cells) by light onset. At maturity these parallel ON and OFF pathways are segregated in the dLGN at the level of single neurons; individual dLGN neurons generally respond to increments or decrements in light but not both. In some species, such as the ferret, dLGN neurons receiving ON input and OFF input reside in two distinct sublaminae within each eye-specific layer, and these sublaminae develop just after eye-specific segregation and before opening. The emergence of On and Off sublaminae before the onset of vision precludes a physiological assessment of whether dLGN neurons transiently receive converging ON and OFF synaptic inputs. However, this is likely because before these On and Off sublaminae form RGC axons initially arborize over both the inner and outer half of each eye-specific layer.

Among the classes of RGCs that project to the dLGN are Y cells which process movement, X cells which are responsible for image acuity, and a heterogeneous population of W cells. Whether individual dLGN neurons initially receive synaptic input from these multiple classes of ganglion cells is unclear. In the primate, however, magnocellular and parvocellular pathways project to distinct regions of the dLGN from early stages as their axons innervate targets. ^, This suggests that during primate development single dLGN neurons may receive inputs from just one class of RGC. This specificity could be due, at least in part, to the generation of different retinal ganglion cell classes at different times during development, and to the fact that the axons of parvo cells reach the dLGN before those of magno cells. In addition, in primates the axons from the two eyes may initially innervate the dLGN in a somewhat eye-specific manner; thus, the primate retinogeniculate connection may require less refinement than that of other mammals.

Interestingly, studies also suggest that once the mature pattern of anatomical and functional connections has been established they must be actively maintained. Taken together, these data indicate that the mature retinogeniculate connection must be sculpted out of an initially over-connected circuit, and that the extent of this refinement may vary from species to species. These data also suggest that retinogeniculate development occurs over several stages beginning with the segregation of eye-specific inputs, followed by a more fine-scale refinement phase that sharpens the retinotopic map, and a final maintenance phase during which this connection remains malleable.

Activity-dependent refinement of retinogeniculate projections

Once it was appreciated that much of the initial development and refinement of retinogeniculate projections occurs before the onset of vision, these findings raised the question of whether synaptic transmission and/or neuronal activity are required for refinement. The first demonstrations that action potentials are required for eye-specific segregation came from studies in which tetrodotoxin (TTX) was used to block sodium channels in fetal cat brain. This activity blockade prevented the formation of eye-specific domains. ^, Further experiments found that spontaneous activity is generated in the retina during eye-specific segregation and when spontaneous retinal activity is disrupted eye-specific layers do not form. In addition, activity disruptions that prevent axon refinement also lead to larger than normal receptive fields.

After eye-specific segregation, neural activity also contributes to the refinement of ON and OFF inputs in the dLGN. In the ferret visual system either blockade of retinal activity or postsynaptic N-methyl- d -aspartate (NMDA) receptor activity disrupts the formation of ON and OFF sublaminae. ^, This suggests that synaptic transmission from the retina to the dLGN is necessary for at least this one aspect of retinogeniculate refinement; although the specific role of synaptic transmission and plasticity in this and other aspects of retinogeniculate refinement warrants closer investigation.

After retinal inputs are segregated within the dLGN neural activity continues to be required for maintaining the precision established during development. For example, blockade of retinal activity after eye-specific layers have formed in the ferret causes the silenced projections to lose the territory that they had previously occupied. Similarly, blockade of late stage activity in mice with TTX disrupts synaptic refinement, preventing the elimination of weak inputs and the strengthening of remaining inputs. In addition, analysis of a mutant mouse that develops excessive retinal activity after eye-specific segregation found that this increased activity is capable of desegregating retinal inputs. This mutant mouse, termed nob1 (no b wave), lacks a protein necessary for photoreceptor to bipolar cell synaptic transmission and at the time when vision through photoreceptors would normally ensue it instead develops abnormally high rates of spontaneous retinal activity. Since spontaneous retinal activity is unaltered in these mice during the period when eye-specific segregation normally occurs, their axons initially segregate normally. ^, However, with the onset of the abnormally high-frequency activity the eye-specific inputs desegregate, leading to increased axonal overlap. In addition to this late requirement for normal spontaneous activity, visual input also appears to play an important role in the maintenance of retinogeniculate refinement. If animals are deprived of visual input when the late stages of within-eye refinement are nearly complete, dLGN neurons will become multiply innervated again, essentially reverting to a more immature innervation state. ^,

Together these experiments indicate that spontaneous activity is required for driving both eye-specific and On–Off segregation and that both spontaneous and visually evoked retinal activity are necessary for maintaining segregation.

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