Mechanisms Mediating Development and Refinement of Retinogeniculate Connections.

摘要

A hallmark of mammalian neural circuit development is the refinement of initially imprecise connections through activity-dependent competition. A prime example of this takes place in the developing visual system where retinal ganglion cell (RGC) axons from the two eyes compete for territory in the dorsal lateral geniculate nucleus (dLGN). Despite numerous experiments indicating that spontaneous spiking activity in the retina drive eye-specific axonal competition, the direct contributions made by synaptic transmission to eye-specific refinement remain unclear. Chapter 2 of this manuscript attempts to narrow this gap. In that study a novel mouse genetic strategy was used to disrupt glutamate release from a defined population of RGCs, the ipsilateral-projecting RGCs. We found that when glutamate release from ipsilateral-RGC axons is reduced, they fail to exclude competing contralateral axons from their target region in the dLGN. Nevertheless, the release-deficient axons both consolidated and maintained their normal amount of dLGN territory in the face of fully active, competing axons. These data demonstrate that during visual circuit refinement glutamate-based competition plays a direct role in removing axons from inappropriate target regions, and they argue that axonal consolidation within appropriate target regions is largely insensitive to synaptic competition. Chapter 3 investigates the roles of two proteins, neuronal pentraxins 1 and 2 (NP1/2), during retinogeniculate development. NP1/2 are hypothesized to play important roles in the development of AMPAR-mediated synaptic transmission and their absence disrupts eye-specific refinement; therefore we hypothesized that NP1/2 might participate in the synaptic mechanisms that refine eye-specific RGC-dLGN projections. Electrophysiological analysis was performed on thalamic slices from mice lacking NP1/2, which showed a specific reduction in AMPAR-mediated synaptic transmission during the period when eye-specific territories form. This was the first demonstration that NP1/2 are required in vivo for the normal development of AMPAR-mediated synaptic transmission and is consistent with a role for NP1/2 in mediating eye-specific refinement through synaptic mechanisms. The basis of the reduced AMPAR currents and their relationship to the structural defects exhibited by NP1/2 KO RGC axons were further explored. Chapter 4 discusses the findings from the two studies and suggests additional experiments that could extend the present findings.