The way a neural circuit functions is largely determined by how it is built. This project aims to elucidate the role of presenilin (PS) in a developing visual system. Although discovered, and named, in the context of Alzheimer's disease, we now know this molecule carries out a multitude of functions that may be important during development. As the catalytic component of ?-secretase, PS has substrates that are involved in neurogenesis, neural differentiation, axon guidance, and synapse formation. This suggests that PS is an important and global molecule for proper neural circuit development. The role of this molecule in neural circuit development and function, however, has not been determined, and is the main objective of this proposal. To provide comprehensive and detailed information about the role of this molecule throughout all stages of nervous system development, we will use Xenopus tadpole visual system as our model. This classic model is especially well-suited to carry out a comprehensive study of PS because it is the only vertebrate model that allows for all stages of neural development to be studied, at the cell, circuit, and behavioral levels, in vivo. To test the role of PS in the development of the tadpole visual system, PS function will be inhibited pharmacologically or genetically, at different key stages of development, and a series of assays to test visual system function at the behavioral, circuit, and cellular level will be carried out. To assess visual system function at the behavioral level, visually guided avoidance behaviors will be assessed using a moving dot assay. To study the effect of altered PS function at the circuit level, light of different intensities is projected onto the retina and the resulting electrical responses of single tectal neurons (neurons that comprise the optic tectum, the visual center of the amphibian brain), recorded. To quantify effects at the cellular level, a series of electrophysiological recordings that are designed to measure many aspects of cellular electrophysiological properties, will be carried out. Several substrates of PS are known to be involved in axon guidance, and proper circuit function requires that axons make it to exact appropriate targets. Our model system is an excellent model to study long distance guidance of axons: retinal ganglion cells in the eye project their axons from the eye to the brain, cross the midline at the optic chiasm, and terminate in the contralateral tectum. To test the role of PS in the process, axons of the retinal ganglion cells in the eye will be imaged, in vivo, and control axons compared to axons in which PS function has been inhibited at various key stages of their journey. Deficits identified in visual system function will continue to be monitored later, in more mature tadpoles and froglets, to determine if deficits occurring during development manifest later in the more mature circuit. Combined, this work will provide a comprehensive and detailed characterization of the role of PS in the development and function of a neural circuit, from the cell to behavioral levels, and add insight about molecular mechanisms that coordinate and regulate proper neural circuit development.

Public Health Relevance

The goal of this project is to provide a comprehensive understanding of the role of presenilin in a developing visual system. Presenilin is an interesting molecule that was discovered, and named, in the context of Alzheimer's disease, but is now known to carry out a myriad of functions that may be important during development. As such, this project is relevant to public health because it provides a new detailed and comprehensive understanding about the molecular mechanisms that underlie normal nervous system development which will help guide the design of improved ways to treat ? and better yet, prevent - neurodevelopmental disorders.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Special Emphasis Panel (ZGM1)
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University of Wyoming
United States
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