Development of a Mathematical Model of Signal Transduction and Adaptation in Mammalian Cone Photoreceptors – ConeModel

Development of a Mathematical Model of Signal Transduction and Adaptation in Mammalian Cone Photoreceptors

The eyes of most vertebrates possess two kinds of photoreceptors: rods for dim-light vision, and cones for daylight and color vision. Rods are highly sensitive to light and can respond to single photons. Cones signal only in brighter light but are more sensitive to change and motion. Whereas rods have a limited ability to adapt and are nearly saturated in daylight, cones remain functional even in the brightest illumination. For this reason, cones are primarily responsible for most of our visual behavior. Despite their importance in our daily lives, much less is known about cones. It is therefore still an open question how the physiological differences between rods and cones arise from differences in their cellular geometry and biochemical signal transduction pathways. For example, it is unclear which mechanisms sustain the remarkable ability of cones to adapt to light, so that they can avoid saturation and continue to function even under the most extreme light conditions. This specific question is related to a much more general and fundamental question in sensory transduction: how do the polarized geometry, the ionic environment, and the properties of the biochemical signal-transduction pathway determine the neuronal response to a stimulus?
Little progress has been made answering this fundamental question for photoreceptors, mainly because of the lack of precise knowledge about cones. A major impediment has been the difficulty of identifying and recording from mouse cones. A recent technical advance in the Fain/Sampath laboratory has now made it possible to target cones reliably in a living preparation and to perform electrophysiological recordings from wild-type and mutant mouse cones, providing an extensive library of unpublished data. Because of the large complexity and synergy in subcellular processes that determine these electrical responses, it is however impossible to extract a quantitative understanding about cone functioning at a molecular level from such data alone. In this project, we therefore propose an interdisciplinary approach to combine these new electrophysiological recordings with modeling, mathematical analysis, and computer simulations to develop a comprehensive understanding of how cones detect light.
As yet, no comprehensive model for cones exists that is comparable to our previously published model of rod photoreceptors. We will use our rod model as a starting point to develop a much more detailed mathematical framework that will allow us to describe both rods and cones. This work will provide the first model of the cone response. We hope also to be able to reduce the difference between the two kinds of photoreceptors to specific parameters in our framework. We will then use this framework to understand how differences in rod and cone responses have arisen as a synergetic effect from differences in their cell geometries and biochemical transduction pathways. This information will provide a precise understanding of how cones adapt and mediate our sensitivity in daylight, which is essential for most of our daily activity. It will also help us understand how rods evolved from cones, and why vertebrate retina is duplex with two fundamentally different systems of light detection.
We propose in addition to perform a variety of simulations which may provide insight into the way sensory transduction is altered in a diseased state, which may help in the design and treatment of photoreceptor dysfunction. Finally, a precise rod and cone model could assist in the design of an electronic replacement of the photoreceptor layer in the retina, which can be implemented as the first component of an electronic (artificial) retina.