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GABA may be key to regenerating human retinas

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 ability — yet.

However, new research into retinal regeneration in zebrafish has identified a signal that appears to trigger the self-repair process. If confirmed by follow-up studies, this discovery raises the possibility human retinas might also be induced to regenerate, naturally repairing damage caused by degenerative retinal diseases and injury. Perhaps even age-related macular degeneration or retinitis pigmentosa.

The research was performed by a team of biologists at Vanderbilt University and is described in a paper titled "Neurotransmitter-Regulated Regeneration in the Zebrafish Retina" published Mar. 9 by the journal Stem Cell Reports.

"The prevailing belief is that the regeneration process in fish retinas is triggered by secreted growth factors, but our results indicate the GABA neurotransmitter might initiate the process instead. All regeneration models assume a retina must be seriously damaged before regeneration takes place, but our study indicates GABA can induce the process in undamaged retinas."

James Patton PhD, Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA; study leader.

It turns out the structure of retinas of fish and mammals are basically the same. Although a fish retina is very thin, less than 0.5 millimeters (0.019685 of an inch), it contains three layers of nerve cells: (1) photoreceptors that detect light, (2) horizontal cells that integrate signals from photoreceptors and (3) ganglion cells which receive visual information and route it to the brain. In addition, retina contain a special adult stem cell, Müller glia, spanning all three layers, providing mechanical support and electrical insulation.

In fish retinas, Müller glia are key in regeneration. When regeneration is triggered, the Müller glia de-differentiate (go from a specialized to a simple state), begin proliferating, and differentiate again to replace damaged nerve cells. Mammal retinas also have Müller glia — but they don't regenerate.

Graduate student Mahesh Rao recognised that GABA — a fast-acting neurotransmitter known for inhibiting synapses in the brain — might trigger retinal regeneration. He was inspired by results of a study on the mouse hippocampus which found GABA controlled stem cell activity.

So Rao, working with Patton and research assistant professor Dominic Didiano, designed a series of experiments on zebrafish, an animal model used to study regeneration. The experiments revealed high concentrations of GABA in the retina keep Müller glia quiescent. The glia begin de-differentiating and proliferating when GABA concentrations drop.

"Last month a paper was published in Cell 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 that neurotransmitter."

James Patton PhD

They tested their hypothesis in two ways: (1) blinding zebrafish then injecting them with drugs to stimulate GABA and by (2) injecting normal zebrafish with an enzyme lowering levels of GABA in their eyes.

Zebrafish blind easily. Placed in total darkness for several days, then suddenly exposed to very bright light, destroys all their photoreceptors. Due to their robust ability to regenerate, however, their eyes recover in just 28 days.

When newly blinded fish were injected with drugs to keep GABA high — regeneration was suppressed.

When normal fish were injected with an enzyme lowering GABA levels, Müller glia began de-differentiating and proliferating — the first stage in the regeneration process.

"Our theory is that a drop in GABA concentration triggers regeneration. It initiates a cascade of events including the activation of Müller glia and production of various growth factors to stimulate cell growth and proliferation. If we are right, it might be possible to stimulate human retinas to repair by treating them with a GABA inhibitor."

James Patton PhD

The researchers' next step is to determine if GABA not only stimulates Müller glia de-differentiation and proliferation, but also differentiation that produces new photoreceptors and other specialized neurons in the retina. They are pursuing this in both zebrafish and mice with a grant from the National Eye Institute's Audacious Goals Initiative.

•Inhibiting GABA or glutamate signaling causes spontaneous Müller glia proliferation
•Activating GABA or glutamate signaling reduces damage-induced proliferation
•Müller glia directly respond to extracellular GABA
•Inhibition of GABA signaling activates regeneration response

Current efforts to repair damaged or diseased mammalian retinas are inefficient and largely incapable of fully restoring vision. Conversely, the zebrafish retina is capable of spontaneous regeneration upon damage using Müller glia (MG)-derived progenitors. Understanding how zebrafish MG initiate regeneration may help develop new treatments that prompt mammalian retinas to regenerate. We show that inhibition of γ-aminobutyric acid (GABA) signaling facilitates initiation of MG proliferation. GABA levels decrease following damage, and MG are positioned to detect decreased ambient levels and undergo dedifferentiation. Using pharmacological and genetic approaches, we demonstrate that GABAA receptor inhibition stimulates regeneration in undamaged retinas while activation inhibits regeneration in damaged retinas.

zebrafish, retina, regeneration, Müller glia, GABA

The research was funded by National Eye Institute grants R01 EYE024354, R21 EY019759 and P30-EY008126.
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Mar 16, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

Different types of nerve cells in the zebrafish retina overlap.
Horizontal cells are shown in red, Muller glia are shown in green.
Image Credit: The Patton Lab, Vanderbilt University


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