Mechanisms and Role of Spontaneous Retinal Waves in Visual Development.

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PROJECT SUMMARY Experiments in this proposal will advance our understanding of mechanisms responsible for the development of precise neural circuitry in the mammalian brain. Patterned activity is critical for normal development of neural circuits, and deficits in activity-dependent circuit refinement are associated with neurodevelopmental disorders such as Fragile X syndrome, autism, and amblyopia. Amblyopia is the most common cause of monocular visual impairment among young and middle-aged adults, with approximately 3 in 100 children effected. Amblyopia is characterized by a range of deficits in spatial vision, spatial contrast sensitivity, and other tasks. However, the mechanisms of this maladaptation are not well understood. We will employ a broad range of techniques, including molecular biological, cell biological, neuroanatomical, electrophysiological and advanced optical imaging techniques in vitro and in vivo. We focus our experiments on neural circuits in the midbrain superior colliculus and visual cortex of the mouse. Beyond the retina, these areas are the largest visual structures in the brain. The superior colliculus is a sensory motor structure that has emerged as an ideal model system for the examination of neural circuit development and function. The visual cortex is a canonical model system for the study of higher order brain function and development in mammals. It is widely hypothesized that molecular cues are responsible for the establishment of gross brain circuit features, and activity dependent processes subsequently refine these circuits to functional precision. The emergence of visual circuit features before the onset of sensory experience suggests that visual map formation is first initiated by activity-independent mechanisms, such as axon guidance molecules, then refined by pre-vision correlated spontaneous activity, and later maintained and sharpened by visual experience after eye-opening. Spontaneous bursting of retinal ganglion cells results in propagating waves of activity that change with age based on their primary excitatory drive. Initially characterized in vitro, stage I waves occur before birth and are mediated by gap junctions between retinal ganglion cells. Stage II occur from birth until around P10 and are mediated by cholinergic starburst amacrine cells. Stage III waves are glutamatergic in origin, with bipolar cells providing the primary excitatory drive onto retinal ganglion cells from P10 until eye-opening. This project aims to examine the specific spatiotemporal features and the underlying cellular mechanisms by which retinal waves are instructive for the development of higher order circuits and neuronal response properties, in both subcortical and cortical circuits, prior to eye opening.