Molecular and functional mechanisms underlying binocular vision

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DESCRIPTION (provided by applicant): The exquisite alignment of projections from the two eyes in central visual structures is fundamental for a precise representation of the visual world. We have discovered that the transmembrane protein Ten_m3 is a critical regulator of this process. Mice that lack Ten_m3 show profound abnormalities in mapping of ipsilateral projections relative to contralateral projections, and marked deficits in visual behavior which are reversed by acute monocular inactivation. This indicates that altered interocular interactions act to suppress vision, and that the upstream cortical circuitry is sufficiently intact to mediate visual behavior in the absence of these interactions. These mice allow the opportunity to not only understand the functional consequences of a binocular mismatch, but to probe the mechanisms which underlie binocular vision itself. We will determine the mechanism by which Ten_m3 regulates axon guidance. The pronounced ipsilateral mistargeting predicts that inputs to V1 will be altered in Ten_m3 null mice. We will use anatomical and functional techniques to determine the distribution of ipsilateral and contralateral inputs to V1. We will test the intriguing prediction that functional ocular dominance columns will form in V1, and assess the role of visual experience in their generation. The data suggest there will be a functional misalignment between the ipsilateral and contralateral inputs to V1. The responses, receptive fields and maps of ipsilateral and contralateral inputs, and their interactions, will be examined using electrophysiological recording, intrinsic signal imaging, and two-photon imaging. We will explore the possibility that altered interocular interactions lead to an exaggerated form of interocular suppression and that V1 is an important locus of this effect. Based on its expression pattern, we propose that Ten_m3 regulates cortical arealization and connectivity and will determine its role in these processes. The intracellular signaling pathways which operate downstream of Ten_m3 are unknown. Our data shows that mice lacking zic4 display the inverse phenotype to Ten_m3 mutants. The nature of the interactions between Ten_m3 and zic4 will be determined and novel components of this signaling pathway identified. These findings will have important implications for understanding how abnormal binocular disparity leads to dysfunction in visual disorders such as strabismus and amblyopia, and for developing strategies for their treatment. PUBLIC HEALTH RELEVANCE: Ten_m3 has been shown to be instrumental in development of the visual system. Improper processing of visual inputs can result in amblyopia, strabismus, or blindness; in addition, deficits in sensory processing have been linked to autism and other disorders of cognitive and social development. The planned experiments promise to elucidate the mechanisms by which Ten_m3 expression affects the development of binocular vision, and thus to provide a novel basis for the design of therapies for visual dysfunction.