Ephrin-As and Patterned Retinal Activity Act Together in the Development of Topographic Maps in the Primary Visual System

Abstract

The development of topographic maps in the primary visual system is thought to rely on a combination of EphA/ephrin-A interactions and patterned neural activity. Here, we characterize the retinogeniculate and retinocollicular maps of mice mutant for ephrins-A2, -A3, and -A5 (the three ephrin-As expressed in the mouse visual system), mice mutant for the ␤2 subunit of the nicotinic acetylcholine receptor (that lack early patterned retinal activity), and mice mutant for both ephrin-As and ␤2. We also provide the first comprehensive anatomical description of the topographic connections between the retina and the dorsal lateral geniculate nucleus. We find that, although ephrin-A2/A3/A5 triple knock-out mice have severe mapping defects in both projections, they do not completely lack topography. Mice lacking ␤2-dependent retinal activity have nearly normal topography but fail to refine axonal arbors. Mice mutant for both ephrin-As and ␤2 have synergistic mapping defects that result in a near absence of map in the retinocollicular projection; however, the retinogeniculate projection is not as severely disrupted as the retinocollicular projection is in these mutants. These results show that ephrin-As and patterned retinal activity act together to establish topographic maps, and demonstrate that midbrain and forebrain connections have a differential requirement for ephrin-As and patterned retinal activity in topographic map development.

Functional Topography and Integration of the Contralateral and Ipsilateral Retinocollicular Projections ofEphrin-A−/−Mice

“…Thus, the functional topography observed here contrasts with anatomical topography in ephrin-A Ϫ/Ϫ mice, which becomes more disordered as additional ephrin-A genes are knocked out (Pfeiffenberger et al, 2006). This discrepancy between anatomical and functional topography is also observed in the visual cortex of ephrin-A Ϫ/Ϫ mice (Cang et al, 2008), which implies that even in the absence of ephrin-As, retinal projections can be topographically refined by neuronal activity.…”

“…The important role of neuronal activity in refining abnormal retinocollicular projections is illustrated in ephrin-A2/A5 Ϫ/Ϫ mice that additionally lack the ␤2 subunit of the nicotinic acetylcholine receptor and, thus, spontaneous retinal activity during development (ephrin-A2/A5/␤2 triple knockout) (Pfeiffenberger et al, 2005(Pfeiffenberger et al, , 2006. In these triple knock-out animals, in contrast to some topographic organization in our double knock-out ephrin-A2/A5 Ϫ/Ϫ mice (Feldheim et al, 2000), the contralateral retinocollicular projection was completely disordered, suggesting that activitydependent refinement compensates for the absence of normal guidance cues.…”

“…In mice lacking ephrin-A2 and/or ephrin-A5, neuronal tracing studies of the contralateral projection have shown that although topographically appropriate projections are present, topographically inappropriate terminations are also observed (Frisen et al, 1998;Feldheim et al, 2000;Pfeiffenberger et al, 2006). Moreover, when spontaneous neuronal activity is prevented in ephrin-A2/A5 Ϫ/Ϫ mice, the retinocollicular projection is completely disordered (Pfeiffenberger et al, 2006), suggesting that neuronal activity significantly refines the abnormal anatomical substrate.…”

“…Moreover, when spontaneous neuronal activity is prevented in ephrin-A2/A5 Ϫ/Ϫ mice, the retinocollicular projection is completely disordered (Pfeiffenberger et al, 2006), suggesting that neuronal activity significantly refines the abnormal anatomical substrate. Here, we use neuronal tracing and electrophysiological mapping of visually evoked responses to characterize the organization of the ipsilateral retinocollicular projection and its integration with the contralateral projection in ephrin-A2 Ϫ/Ϫ and ephrin-A2/ A5 Ϫ/Ϫ mice.…”

Self‐organization in the developing nervous system: Theoretical models

“…However, blocking activity in addition affected wave structure and prevented eye-specific segregation as in animals with normal ephrin expression (Huberman et al, 2002;Rossi et al, 2001). A similar pattern was observed by Pfeiffenberger et al (2005b) who analyzed abnormalities in retinogeniculate and retinocollicular mapping in combined ephrin-A2/A3/A5 and ␤2 mutants. These studies suggest an independent action of molecular cues and activity in map formation where ephrin/Eph gradients are required for establishing the coarse map topography and activity is needed to refine axonal arbors.…”