A new experiment with zebrafish uncovers the mechanism behind fish eye regeneration.
As we age, our eyesight declines and we may find that reading the daily newspaper is not as easy as it used to be. Apart from this normal development - called presbyopia - there are other eye conditions that come as a result of the eye's degeneration.
Age-related macular degeneration is quite common and is the leading cause of vision loss among people aged 50 and older. In the condition, the macula - a spot located near the center of the retina - is damaged, which causes blurred or distorted vision.
Retinitis pigmentosa is another group of eye disorders that affect how the retina responds to light. The condition is genetic and involves a gradual, but not total, loss of vision.
New research investigates the regenerative ability of fish eyes. The eyes of fish have the ability to recover from damage and restore sight within a few weeks, and the new research provides insights that could one day help researchers induce self-regeneration to the human eye. This could help to repair the damage caused by diseases such as age-related macular degeneration or retinitis pigmentosa.
The new study was conducted by researchers at Vanderbilt University in Nashville, TN, and led by James Patton, Stevenson Professor of Biological Sciences at Vanderbilt. The results were published in the journal Cell Reports.
How fish eyes regenerate
The researchers started out from the hypothesis that a neurotransmitter might be responsible for retinal regeneration in fish. Fish and mammals have a very similar retinal structure, so Mahesh Rao - a graduate student and study co-author - thought of extrapolating the results of a mouse study and test them on zebrafish.
The mouse study that triggered Rao's hypothesis discovered that this neurotransmitter - called GABA - controlled the activity of some retinal stem cells. GABA neurotransmitters normally act as inhibitors, lowering a neuron's ability to excite the neurons around it. GABA neurotransmitters are very prevalent in the brain, occurring in 30 to 40 percent of all the synapses.
Among other cells, the retina also contains a type of stem cell called Müller glia. In humans and other mammals, these cells provide "architectural support" that traverse all of the retina's layers - but in fish, these glial cells also play a crucial role in regeneration.
During the regenerative process, these cells undergo a form of regression called dedifferentiation, meaning that they go from a specialized state back to a more general, simpler state. They then differentiate again, but this time into replacements for the nerve cells that were damaged.
Neurotransmitter may trigger regeneration process
In their zebrafish experiment, Rao and colleagues tested their hypothesis by alternately stimulating and lowering the production of GABA with the help of an enzyme they injected.
They found that high levels of GABA in the retina keep the Müller glia inactive. When retinal GABA levels decrease, the glial cells start to dedifferentiate and then proliferate, as part of the regenerative process.
The study's lead author explains the findings and the contribution of the research:
"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 [...] 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."
In the future, the researchers plan to investigate whether GABA is also responsible for the cell differentiation that creates new photoreceptors and other specialized retinal nerve cells.