Pacemakers of Cholinergic Wave Activity in the Developing Retina

项目总结

PROJECT SUMMARY Before the emergence of vision, spontaneous retinal wave activity is essential for retinal layer-specific angiogenesis and dendritic maturation of retinal ganglion cells, as well as for the refinement of eye-specific segregations and retinotopic maps. A subpopulation of retinal amacrine interneurons, called starburst amacrine cells, initiate and propagate retinal waves through recurrent cholinergic connections called cholinergic retinal waves. However, the mechanisms underlying cholinergic wave initiation and propagation are poorly defined. Currently, the most urgent priority is to define how cholinergic waves are initiated to create a framework for understanding their downstream propagation. This project's objective is to identify a subset of starburst amacrine cells that serve as cholinergic wave pacemakers and the mechanisms by which pacemaker starburst amacrine cells generate these waves. Preliminary data from the PI's laboratory demonstrate that it is feasible to identify pacemaker starburst amacrine cells and the sufficiency of a single pacemaker starburst amacrine cell to initiate a wave. Wave generation requires activation of voltage-dependent calcium channels. These novel findings lead to the central hypothesis: single pacemaker starburst amacrine cells initiate waves by a calcium-dependent mechanism. To test this hypothesis, the team will determine the distribution and properties of cholinergic wave pacemakers (Aim 1), and identify the calcium-dependent mechanisms of cholinergic wave generation (Aim 2). The work on understanding the identity and features of pacemaker starburst amacrine cells and the ionic mechanisms of cholinergic retinal wave generation will advance knowledge of how retinal waves mediate vascular and neuronal development of the retina as well as eye-specific segregation and retinotopic map refinement in the visual centers of the brain.