Restoring vision loss in patients with retinal degenerative disorders, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RD) is a goal of many researchers, who are using different therapeutic strategies, including retinal prosthetic implants, optogenetics, stem cell treatments, and gene therapy. A novel approach is the use of a pharmacological agent that acts on synaptic receptors to facilitate transmission of residual, visual signals in the degenerate retina. This approach has not been considered previously. However, recently I discovered that when a GABAc receptor antagonist (TPMPA) is applied to the retina of a P23H rat (model of retinitis pigmentosa), retinal ganglion cells (RGCs) became more sensitive to a light stimulus. The working hypothesis is that there is an increase in tonic inhibition at the axon terminals of bipolar cells in the degenerate retina, and this increased inhibition impedes transmission of photoreceptor signals to RGCs. An alternative to blocking GABAergic receptors on axon terminals of bipolar cells is to block the release of GABA onto the terminals. The metabotropic glutamate type 1 (mGlu1) receptor is reported to modulate GABA release onto bipolar cell axon terminals. I found that the mGlu1 receptor antagonist JNJ16259685 also increased light sensitivity of RGCs in the P23H rat retina. In the proposed study, I plan to follow up on these observations by further evaluating the effects of these receptor antagonists on the receptive field properties of P23H rat RGCs, and to validate these findings in another animal model of retinal degeneration. There are three specific aims in this proposed project.
Each specific aim will entail the recording of light responses from RGCs with multielectrode arrays.
Aim 1 will examine the effects of blocking GABAc receptors on the receptive field properties of P23H rat RGCs, and Aim 2 will examine the effects of blocking mGlu1 receptors.
Aim 3 will determine whether the effects of the GABAc and mGlu1 receptor blockers are reproducible in another model of retinal degeneration (the rd10 mouse). The findings will provide important information on how these neurotransmitter receptor antagonists may alter visual perception in patients with retinal degeneration.
The retinal degenerative diseases age-related macular degeneration (AMD) and retinitis pigmentosa (RP) account for ~40% of the cases of legal blindness within the VA system. Restoring vision loss in these patients is a goal of many researchers, who are using different therapeutic strategies, including retinal prosthetic implants, optogenetics, stem cell treatments, and gene therapy. A novel approach is the use of a pharmacological agent that acts specifically on synaptic receptors to facilitate transmission of residual, visual signals in the retinas of thes patients. The long-term objective is to extend the period of useful vision in patients with retinal degenerative disorders by increasing light responsiveness of retinal ganglion cells (RGCs), the output neurons of the retina, through the use of a pharmacological agent that acts on the inner retinal circuitry.
| Jensen, Ralph J (2016) Effects of Antipsychotic Drugs Haloperidol and Clozapine on Visual Responses of Retinal Ganglion Cells in a Rat Model of Retinitis Pigmentosa. J Ocul Pharmacol Ther 32:685-690 |
| Jensen, Ralph (2015) Effects of Dopamine D2-Like Receptor Antagonists on Light Responses of Ganglion Cells in Wild-Type and P23H Rat Retinas. PLoS One 10:e0146154 |
