Director: Neal S. Peachey, Ph.D.
Department of Ophthalmic Research
Cole Eye Institute
9500 Euclid Avenue, i32
Office telephone: 216.445.1942
Members of the Peachey lab, from left, are Sherry Ball, Ph.D., Elisa Bala, M.D., Jiang Wu, M.D., Neal Peachey, Ph.D., Minzhong Yu, M.D., Ph.D., and Ruth Yarnevic, B.S.
Goals and projects
Mouse Retinal Electrophysiology
As the mouse has become the premiere laboratory model for retina research, it has become increasingly important to develop objective measures of retinal function that can be used to evaluate the function of different classes of retinal cells.
We have adopted a noninvasive technique that has been used to investigate the origins of visual dysfunction in human hereditary and acquired retinal disorders. The ERG (electroretinogram) is the mass electrical response of the retina to light. In the research laboratory, the response provides a sensitive means to evaluate experimental therapies for retinal disease, which can be repeated at different time points on the same animal. In addition, the ERG is used to characterize the effects of pharmacological manipulation or introduction of gene defects.
By controlling the conditions under which stimuli are presented, the activity of the rod or cone visual pathways can be monitored independently. Based on contributions from a number of investigators, it is now possible to relate the different components that comprise the rod-mediated ERG to the major cell types of the rod visual pathway. This knowledge has led to a comprehensive model of the rod ERG which finds wide application.
In comparison, the components that underlie the mouse cone ERG have not been identified. As a major focus of the CEI research program is macular degeneration, we are using pharmacological agents that block transmission from cone photoreceptors to second order neurons that comprise the cone pathway (cone depolarizing bipolar cells, and the cone hyperpolarizing bipolar cells) to determine the contribution of these cell types to the cone ERG. At the completion of this work, we will define a model capable of relating the components of the cone ERG to the cells that comprise the cone pathway.
In collaboration with Alan D. Marmorstein, Ph.D., we have also developed a noninvasive procedure for recording the electrical response of the retinal pigment epithelium (RPE) to light. In comparison to the rod and cone ERGs mentioned above, the RPE components are very slow, necessitating dc-recording. This procedure will be particularly useful in characterizing rodent models expressing mutant RPE genes.
Mouse Models of Congenital Stationary Night Blindness
For the past several years, we have been working with a naturally occurring mouse model of complete congenital stationary night blindness (CSNB1). This mutant, named nob, involves a defect in transmission from rod and cone photoreceptors to depolarizing bipolar cells. The nob mouse carries a mutation in the nyctalopin gene, which is also the gene involved in human CSNB1. As the function of nyctalopin is unknown, studies are under way to define the role of this protein in normal retinal function and development.
We have also identified a mouse model of another form of human disease, incomplete CSNB (CSNB2). The mouse model involves the CNS-specific deletion of the gene encoding a subunit of the L-type calcium channel that normally regulated release of glutamate at the photoreceptor terminal. These mice develop the same phenotype seen in patients with CSNB2, which involve mutations in the a 1F subunit. Studies are under way to define the role of L-type calcium channels in ribbon synapse formation.
Evaluation of the Retina with a Sub-retinal Microphotodiode Array
This project concerns the tissue compatibility of a subretinal microphotodiode array that has been developed in an attempt to restore vision in patients blinded by diseases causing photoreceptor degeneration. In these diseases, only the photoreceptors degenerate, sparing the inner retinal neurons. The microphotodiode approach relies on electrical stimulation of these inner retinal layers to propagate the visual signal centrally.
In the course of evaluating several implant designs, we have developed a body of data indicating that the implant has good biocompatibility and have found that the use of specific materials for implant fabrication results in a device that will respond consistently for up to 3 years following implantation. While the implant induces disorganization of the inner retinal cell layers, there is no loss of inner retinal neurons in the implanted retina. In addition, the use of cytochemical markers has identified subtle but reproducible changes in the distribution of inhibitory neurons in the inner retina.
We are trying to determine the time course over which these changes occur. The data derived from these studies will provide valuable information on how the inner retina responds to the implant, and may also define areas for implant design improvements.