Caption: Image showing how two different types of nerve cells in the zebrafish retina overlap. Horizontal cells are shown in red, Muller glia are shown in green. Credit: The Patton Lab/ Vanderbilt University

Researchers are one step closer to discovering what allows fish to regenerate their eyes—and someday potentially applying that knowledge to humans.

Researchers from Vanderbilt University are attempting to confirm the identification of a newly discovered signal that triggers the self-repair process in Zebrafish.

 “The prevailing belief has been that the regeneration process in fish retinas is triggered by secreted growth factors, but our results indicate that the neurotransmitter GABA might initiate the process instead,” James Patton, Stevenson Professor of Biological Sciences at Vanderbilt, who directed the study, said in a statement. “All the regeneration models assume that a retina must be seriously damaged before regeneration takes place, but our studies indicate that GABA can induce this process even in undamaged retinas.”

By better understanding fish retina regeneration, researchers hope to someday be able to induce human retinas to regenerate, naturally repairing damage caused by degenerative retinal diseases and injury, including age-related macular degeneration and retinitis pigmentosa.

The structure of the retinas of fish and mammals are basically the same. The retina is very thinless than 0.5 millimeters thick—and contains three levels of nerve cells: photoreceptors that detect the light, horizontal cells that integrate the signals from the photoreceptors and ganglion cells that receive the visual information and route it to the brain.

The retina also contains a special type of adult stem cell—Müller glia—that span all three layers and provide mechanical support and electrical insulation. In fish retinas, they also play a crucial role in regeneration because when regeneration is triggered the Müller glia dedifferentiate, begin proliferating and then differentiate into replacements for the damaged nerve cells.

Graduate student Mahesh Rao believed that GABA—normally a fast-acting neurotransmitter best known for its role of calming nervous activity by inhibiting nerve transmission in the brain—might be the trigger for retinal regeneration.

The researchers designed a series of experiments with zebrafish, which determined that high concentrations of GABA in the retina keep the Müller glia quiescent and that they begin dedifferentiating and proliferating when GABA concentrations drop.

“Last month a paper was published in the journal Cell that reports GABA levels play a central role in the regeneration of pancreas cells,” Patton said. “We now have three instances where GABA is involved in regeneration - the hippocampus, the pancreas and the retina—so this could be an important, previously unknown role for the neurotransmitter.”

The research team tested this hypothesis by blinding zebrafish and injecting them with drugs that stimulate GABA production, and by injecting normal zebrafish with an enzyme that lowers the GABA levels in their eyes.

Zebrafish are easily blinded and if they are in total darkness for several days and then exposed to very bright light, all the photoreceptors in their retinas are destroyed. However, because of their robust regenerative ability, their eyes recover in just 28 days. When the biologists injected drugs that kept GABA concentrations in the retinas of newly blinded fish at a high level, they found that it suppressed the regeneration process.

However, when they injected an enzyme that lowers GABA levels in the eyes of normal fish they found that the Müller glia began dedifferentiating and proliferating, the first stage in the regeneration process.

“Our theory is that a drop in GABA concentration is the trigger for regeneration,” Patton said. “It initiates a cascade of events that includes the activation of the Müller glia and the production of various growth factors that stimulate cell growth and proliferation.

“If we are correct, then it might be possible to stimulate human retinas to repair themselves by treating them with a GABA inhibitor.”

The researchers will now determine if GABA not only stimulates Müller glia dedifferentiation and proliferation but also causes the differentiation that produces new photoreceptors and the other specialized neurons in the retina in both mice and the zebrafish.