Evidence for an Instructive Role of Retinal Activity in Retinotopic Map Refinement in the Superior Colliculus of the Mouse

Abstract

Although it is widely accepted that molecular mechanisms play an important role in the initial establishment of retinotopic maps, it has also long been argued that activity-dependent factors act in concert with molecular mechanisms to refine topographic maps. Evidence of a role for retinal activity in retinotopic map refinement in mammals is limited, and nothing is known about the effect of spontaneous retinal activity on the development of receptive fields in the superior colliculus. Using anatomical and physiological methods with two genetically manipulated mouse models and pharmacological interventions in wild-type mice, we show that spontaneous retinal waves instruct retinotopic map refinement in the superior colliculus of the mouse. Activity-dependent mechanisms may play a preferential role in the mapping of the nasal-temporal axis of the retina onto the colliculus, because refinement is particularly impaired along this axis in mutants without retinal waves. Interfering with both axon guidance cues and activity-dependent cues in the same animal has a dramatic cumulative effect. These experiments demonstrate how axon guidance cues and activity-dependent factors combine to instruct retinotopic map development.

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

“…To determine whether ␤2-dependent retinal activity is responsible for the remaining topography observed in ephrin-A2/ A3/A5 tkos, we compared the topographic maps of wild-type, ␤2 Ϫ/Ϫ , ephrin-A2/A5-dko-␤2 ϩ/Ϫ , and ephrin-A2/A5,␤2 tko mice. Similar to what has been seen previously with anatomical tracing at P14 and P21 (Grubb et al, 2003;Chandrasekaran et al, 2005), we see that adult mice mutant for ␤2 have defects in RGC termination refinement, resulting in TZs that are larger and more diffuse than wild type ( Fig. 5; supplemental Fig.…”

“…As shown previously at P14 and P21, we found that DiIlabeled subsets of RGCs in adult ␤2 mutants result in TZs that are positioned in the topographically correct locations of the SC and dLGN, but are larger and more diffuse. Although larger, the overall shape of the TZs in ␤2 mutants were similar to wild type, suggesting that ␤2-dependent mapping mechanisms may act along both the N-T and D-V mapping axis (Grubb et al, 2003;McLaughlin et al, 2003;Chandrasekaran et al, 2005) (Fig. 5; supplemental Fig.…”

“…Much recent work has used mice mutant for the ␤2 subunit of the nAChR as a model to study the role of retinal waves in visual map development (Rossi et al, 2001;Muir-Robinson et al, 2002;Grubb et al, 2003;McLaughlin et al, 2003;Chandrasekaran et al, 2005). ␤2 Ϫ/Ϫ mice have similar levels of spontaneous retinal activity as wild type; however, they do not form retinal waves during the first postnatal week.…”

“…These mice also have defects in axonal refinement, which result in minor mapping errors in the retinal projections to the SC and dLGN. Previous work using physiological recordings of visual responses have shown that ␤2 mapping errors are more severe along the N-T axis than the D-V mapping axis (Muir-Robinson et al, 2002;Grubb et al, 2003;McLaughlin et al, 2003;Chandrasekaran et al, 2005). To determine whether ␤2-dependent retinal activity is responsible for the remaining topography observed in ephrin-A2/ A3/A5 tkos, we compared the topographic maps of wild-type, ␤2 Ϫ/Ϫ , ephrin-A2/A5-dko-␤2 ϩ/Ϫ , and ephrin-A2/A5,␤2 tko mice.…”

“…During the first postnatal week in mice, correlations in retinal ganglion cell (RGC) firing arise from nicotinic acetylcholine receptor (nAChR)-dependent retinal waves; in the absence of the ␤2 subunit of this receptor, waves are disrupted, resulting in minor N-T topographic mapping errors in both the retinocollicular and retinogeniculate projections (Rossi et al, 2001;Grubb et al, 2003;McLaughlin et al, 2003;Cang et al, 2005b;Chandrasekaran et al, 2005). These mapping errors raise the possibility that the remaining topography observed in ephrin-A2/A5 double knock-outs (dkos) could be partly attributable to the presence of patterned retinal activity.…”