Light-sensitive molecules that stimulate a neural response in the cells of the retina and brain could be the first step toward overcoming degenerative eye diseases or quieting epileptic seizures. Scientists at the University of Illinois at Chicago are working to develop such molecules, which — when injected into the eye — can find and attach to inner retinal cells, and then initiate a signal that is sent to the brain. Dr. David Pepperberg, professor of ophthalmology and visual sciences, UIC. Courtesy of UIC Photo Services/Roberta Dupuis-Devlin. Macular degeneration, the leading cause of vision loss in people over 50, is caused by loss of light-sensitive cells in the retina — the rods and cones. “The rods and cones, which absorb light and initiate visual signals, are the broken link in the chain, even though what we call the ‘inner cells’ of the retina, in many cases, are still potentially capable of function,” said David Pepperberg, professor of ophthalmology and visual science at the university’s College of Medicine. “Our approach is to bypass the lost rods and cones by making the inner cells responsive to light.” The team synthesized new compounds built on the anesthetic agent propofol, a small molecule that binds to a receptor-protein on nerve cells. The receptor is ordinarily activated by the neurotransmitter GABA, and when so activated it opens a channel in the membrane of the cell, initiating a signal that propagates to other nerve cells. The researchers added a light-sensitive chemical component to the propofol molecule so that, when struck by light of different wavelengths, the molecule changes shape and functions as a light-triggered on-off switch for these receptors. The compound, MPC088, was tested in three types of cells: retinal ganglion cells, the nerve cells that send visual signals from the retina to the brain via the optic nerve; Purkinje neurons from the cerebellum; and non-nerve cells that were engineered to produce and install the GABA receptor in the membrane. MPC088 binds to the receptor, making it far more responsive to GABA, the scientists found. At appropriate wavelengths, light converts the compound to an inactive form and back again, reducing and then restoring the receptor’s high sensitivity to GABA. This opens the membrane channel to initiate the neural signal. “Putting it all together, we have a compound that dramatically regulates, in light-dependent fashion, the GABA receptors of both an engineered receptor system and native receptors of retinal ganglion cells and brain neurons,” Pepperberg said. The experiments on the Purkinje neurons “showed we were able to go beyond visual systems,” he said, and demonstrate that “photo-regulation may also have potential as a therapeutic for epilepsy, a class of diseases that involves abnormal excitatory activity in the brain.” Epileptic seizures begin in a defined region of the brain, and it may be possible to introduce the photoswitching compound and a very thin lightguide into this region, Pepperberg said. “Because GABA receptors are typically inhibitory, introducing light of the appropriate wavelength into the region as the seizure begins and activating the GABA receptors could have the effect of turning off the seizure.” The experiments were conducted in collaboration with neurobiologist Thomas Otis at UCLA. The findings were published in Nature Communications (doi:10.1038/ncomms2094). The Illinois team also developed a molecular switch related to MPC088 that permanently anchors a genetically engineered GABA receptor, demonstrating the possibility that a light-sensitive molecule could be introduced into the eye or brain to modify GABA receptors and act as a photoswitch. “Our work opens up new avenues for not only the retinal application but also diseases of the central nervous system where a dysfunction or deficiency of GABA activity is a key problem,” he said. For more information, visit: www.uic.edu