Mechanisms of Synaptic Specificity in Visual Circuits

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ABSTRACT Efficient sensory processing requires the development of precisely wired circuits. Sensory deficits are common in neurodevelopmental disorders (NDDs), such as fragile X syndrome (FXS), underscoring the importance of proper wiring. Despite this, the mechanisms underlying precise sensory circuit wiring and the etiology of sensory dysfunction in NDDs remain poorly understood, precluding development of effective therapies. To address these gaps in knowledge, we have utilized the visual circuitry of the mouse superior colliculus (SC) to elucidate fundamental mechanisms of circuit wiring and uncovered novel sub-circuit-specific visual deficits in FXS mice (Fmr1-/y). Specifically, we will focus on the mechanisms by which topographic maps of space encoded by retinal ganglion cells (RGCs) in the eye and Layer 5 neurons in primary visual cortex (L5V1) are formed in the SC. Previous studies by us and others suggest that each stage of visual circuit development in the SC - RGC mapping, visual map alignment, and circuit consolidation - is dependent on neuronal activity; however, the mechanisms underlying each are poorly understood. Based on our previous and preliminary data, we propose a model in which the activity-dependent mechanisms underlying each stage of visual circuit development in the SC are distinct. We will test this model in three specific aims, leveraging a unique combination of cutting-edge techniques and novel genetic mouse models. In Aim 1, we will test previously developed computational models of L5V1 alignment by manipulating neuronal activity in the SC (Aim 1A) or retina (Aim 1B) and evaluating changes in topographic organization and visual function in the SC. In Aim 2, we will determine when and where Fmr1 is required during visual circuit development in the SC. Specifically, we will elucidate the stage-specific roles of Fmr1 in the development and maintenance of visual map alignment (Aim 2A) and maturation of visual function in the SC (Aim 2B), as well as the region-specific roles in each (Aim 2C). In Aim 3, we will build on our exciting preliminary data, suggesting that visual experience and Fmr1 may interact to regulate the maintenance and/or maturation of visual circuits in the SC. To test this possibility, we will determine the requirement of visual experience for visual circuit organization and function in control (Aim 3A) and Fmr1-/y (Aim 3B) mice. These studies will be complemented with those exposing mice to a visually-enriched environment to test the possibility that it may rescue deficits observed in Fmr1-/y mice (Aim 3C). These studies will uncover fundamental mechanisms of sensory circuit formation and establish a platform for elucidating the molecular underpinnings of activity-dependent wiring. Further, we will gain critical insight into the etiology of sensory dysfunction in FXS, the treatment of which could have reverberating positive impacts on deficits in social communication, anxiety, and intellectual development.