GABA and Retinal Regeneration in Zebrafish

Researchers here investigate the mechanisms by which zebrafish can regenerate their retina, a form of regrowth that does not occur in mammals. This is one part of much broader efforts to understand whether or not the basis for the proficient regeneration of organs observed in zebrafish also exists in mammals, part of a shared evolutionary heritage from common ancestors, but suppressed in mammalian species. There is at this point no real consensus on the odds, nor enough information to estimate how hard it might be to safely coerce mammalian tissues into zebrafish-like regenerative prowess.

If you were a fish and your retina was damaged, it could repair itself and your vision would be restored in a few weeks. Sadly, human eyes don't have this beneficial ability. However, new research into retinal regeneration in zebrafish has identified a signal that appears to trigger the self-repair process. And, if confirmed by follow-up studies, the discovery raises the possibility that human retinas can also be induced to regenerate, naturally repairing damage caused by degenerative retinal diseases and injury, including age-related macular degeneration and retinitis pigmentosa. "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. 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."

It turns out that the structure of the retinas of fish and mammals are basically the same. Although the retina is very thin - less than 0.5 millimeters thick - it contains three layers 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. In addition, the retina contains a special type of adult stem cell, called Müller glia, that span all three layers and provide mechanical support and electrical insulation. In fish retinas, they also play a key role in regeneration. When regeneration is triggered, the Müller glia dedifferentiate (regress from a specialized state to a simpler state), begin proliferating, and then differentiate into replacements for the damaged nerve cells. Müller glia are also present in mammalian retinas, but don't regenerate.

Reseachers 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. They tested their hypothesis in two ways: 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. 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. On the other hand, 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. 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. Last month a paper was published that reports GABA levels play a central role in the regeneration of pancreas cells. 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."



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