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.

The regulation of NMDA receptor (NMDAR) subunit composition and expression during development is thought to control the process of thalamocortical afferent innervation, segregation, and plasticity. Thalamocortical synaptic plasticity in the mouse is dependent on NMDARs containing the NR2B subunit, which are the dominant form during the "critical period" window for plasticity. Near the end of the critical period there is a gradual increase in the contribution of NR2A subunits that happens in parallel to changes in NMDAR-mediated current kinetics. However, no extension of the critical period occurs in NR2A knockout mice, despite the fact that NMDA subunit composition and current kinetics remain immature past the end of the critical period. These data suggest that regulation of NMDAR subunit composition is not essential for closing the critical period plasticity window in mouse somatosensory barrel cortex.

Retinal ganglion cells (RGCs) are the first cell type to differentiate during retinal histogenesis. It has been postulated that specified RGCs subsequently influence the number and fate of the remaining progenitors to produce the rest of the retinal cell types. However, several genetic knockout models have argued against this developmental role for RGCs. Although it is known that RGCs secrete cellular factors implicated in cell proliferation, survival, and differentiation, until now, limited publications have shown that reductions in the RGC number cause significant changes in these processes. In this study, we observed that Math5 and Brn3b double null mice exhibited over a 99% reduction in the number of RGCs during development. This severe reduction of RGCs is accompanied by a drastic loss in the number of all other retinal cell types that was never seen before. Unlike Brn3b null or Math5 null animals, mice null for both alleles lack an optic nerve and have severe retinal dysfunction. Results of this study support the hypothesis that RGCs play a pivotal role in the late phase of mammalian retina development.

Development of the retino-collicular pathway has served as an important model system for examining the cellular mechanisms responsible for the establishment of neuronal maps of the sensory periphery. A consensus has emerged that molecular or chemical cues are responsible for the initial establishment of gross topography in this map, and that activity dependent factors sharpen this initial rough topography into precision. However, there is little evidence available concerning the biochemical signaling mechanisms that are responsible for topographic map refinement in the retino-collicular system. Using a combination of anatomical and biochemical techniques in normal and mutant mice, we provide evidence that Ca2+/Calmodulin regulated Adenylate Cyclase 1 (AC1), which is strongly expressed in the superficial layers of the colliculus, is an important downstream signaling agent for activity dependent map refinement in the superior colliculus.