In the retina, death of photoreceptors due to injury or disease leads to irreversible loss of vision. Loss of photoreceptors is often followed by destructive remodeling of the inner retinal layers that leads to abnormal retinal structure and function. Recently, it has been discovered that selective destruction of a small patch of photoreceptors leaving the inner-retinal neurons intact, leads to migration of the photoreceptors from outside of the lesioned area into the lesion over the period of a few months, thereby restoring retinal continuity. Our pilot data shows that as a result of this process retinal sensitiity in the initial blind spot introduced by photocoagulation can be restored. Moreover, our observations indicate that migrating photoreceptors establish new synaptic connections with bipolar cells in the lesion. These findings demonstrate that retina has the potential for constructive plasticity never observed or even suspected before. Our goal is to establish the mechanism and the limits of this new exciting phenomenon. In particular, the main hypothesis we propose to test is that the healthy photoreceptors migrate inside the lesion and establish new and appropriate connections to the deafferented retinal circuitry inside the lesion. We will test this hypothesis by characterizing functional and anatomical changes induced by selective photocoagulation through multielectrode array recordings of retinal activity and antibody labeling of various retinal neuronal types and synapses. The phenomenon of the constructive retinal plasticity becomes an extremely useful model for understanding the mechanisms of the development of the intricate and specific retinal connectivity in the adult mammalian retina. Of immediate clinical importance is that the results of the proposed research will enable development of novel approach to retinal photocoagulation that will avoid deleterious side effects of the current standard of care, such as scotomata and scarring. Retinal photocoagulation is widely used to treat various retinopathies and its improvement will affect millions of patients worldwide. Results of the research may also provide insights into processes of functional integration of transplanted photoreceptors or stem cells into the adult retina.

Public Health Relevance

In the retina, death of photoreceptors due to injury or disease often leads to irreversible loss of vision. We will investigate the newly discovered phenomenon of photoreceptors migration and rewiring that may enable restoration of visual function in retinal lesions. This new phenomenon has crucial implications for development of novel approach to retinal photocoagulation that will avoid deleterious side effects of the current standard of care, such as scotomata and scarring and will also provide insights into processes of functional integration of photoreceptors or stem cells transplanted into the adult retina.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY023020-02
Application #
8601082
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Greenwell, Thomas
Project Start
2013-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$448,606
Indirect Cost
$99,702
Name
University of California Santa Cruz
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
Sher, Alexander; Jones, Bryan W; Huie, Philip et al. (2013) Restoration of retinal structure and function after selective photocoagulation. J Neurosci 33:6800-8