What are the molecular mechanisms that control the formation of visual circuits? Throughout the mammalian central nervous system, the most salient structural correlate of synaptic specificity is laminar specificity: neurons confine their axonal and dendritic arbors to particular layers and thereby, synaptic partners, within a given target. In this proposal, we will focus on understanding how alpha and beta retinal ganglion cell (RGC) types form their precise synaptic connections in the deep and superficial layers of the superior colliculus respectively. Precise wiring of RGCs is critical for proper motion and pattern visual perception, but the molecular mechanisms that dictate how these two major retinal ganglion cell classes connect to their appropriate laminar target neurons are still mysterious. We hypothesize that the genes responsible for laminar-specific synaptic choices of RGCs will be selectively expressed by these two main classes of RGCs during the developmental period when their specific laminar connections are forming. In our preliminary studies, we have identified specific markers of alpha and beta RGCs as well as two new mouse strains that express green fluorescent protein specifically in each of these RGC classes. We will use these mice to address the following questions: (1) What is the genetic profile associated with these two major classes of functionally distinct RGCs?, and (2) What are the molecular cues that direct axons arising from these functionally distinct classes of RGCs, into anatomically distinct layers within their major target, the superior colliculus? We will then use this information to address a longstanding question about the development of laminar specificity: do RGCs form connections in their target laminae that are initially precise or instead do they form connections that are initially diffuse and then eliminate inappropriate connections? Our ultimate goal is to understand how precise visual synaptic connections form during development and to extend those findings into an understanding of how to induce visual system connections to regenerate properly after injury in ocular diseases including glaucoma, retinal ischemia, and optic neuritis. An understanding of the molecular mechanisms that control the formation of visual circuits will allow us to develop new treatments to promote their repair and regeneration in order to restore vision in glaucoma, optic neuropathy, and after injury. ? ? ?
