Department of Physiology & Biomedical Engineering

University of Arizona

Tuscon, Arizona

BASIC RESEARCH PROJECT

Investigation and modulation of inner retinal dysfunction in diabetes

Research Interests

Visual deficits in the function of dim light-activated rod pathways are some of the earliest identifiable retinal problems in diabetic patients. Electrical recordings from retinas show dysfunction in the inner retina – the neurons that respond to inputs from rod and cone photoreceptors and relay information to the brain. These deficits are tied to the development of serious diabetic retinal problems. Dr. Eggers’ research has shown that deficits in the responses of light of neurons in the inner retina that are part of the dim light rod pathway are not due to cell death, but the mechanism is unknown. Dopamine is released by dopaminergic amacrine cells to allow the retina to adapt to increasing background light levels. Diabetic retinas have low dopamine levels and supplementation of dopamine can reduce inner retinal deficits in diabetes. We are experts in rod pathway signaling and will determine if this pathway is specifically vulnerable to diabetic damage and identify the mechanism of dysfunction to develop targeted therapeutics to prevent the neuronal progression of vision loss.

Plans for 2024

The Eggers’ lab plans to build on their 2023 results by using the in vitro ERG to determine if dopamine-mediated light adaptation is reduced in the diabetic retina, as a result of lower dopamine release and receptor sensitivity. In addition, they plan to complete their studies on dopamine release in the diabetic retina.

Specific Aims: 1: Determine if diabetes induced reduction in dopamine levels reduces dopamine receptor sensitivity of the inner retinal rod pathway. We hypothesize that reduced dopamine levels in early diabetes change the sensitivity of neuron’s responses to dopamine. We will measure the responses of individual retinal neurons to light and determine how dopamine receptor agonists modulate them.

2: Determine if diabetes reduces the release and retinal function of dopamine in light adaptation. We hypothesize that lowered diabetic retinal dopamine reduces retinal dopamine release and adaptation to increased light levels. We will measure neuron and dopamine release in response to increasing background light levels.

Progress in 2023

In 2023, Dr. Eggers’ lab completed studies showing that both dopamine D1 and D4 receptors are less sensitive in the diabetic retina using the in vitro ERG. This was presented at ARVO and submitted for publication. The team also finalized methodology for measuring dopamine release from the diabetic retina using HPLC-mass spectrometry and have preliminary data that dopamine release is lower in the diabetic retina.

Electrical recordings from retinas show dysfunction in the inner retina – the neurons that respond to inputs from rod and cone photoreceptors and relay information to the brain. These deficits are tied to the development of serious diabetic retinal problems. Dr. Eggers’ lab has shown that deficits in the responses of light of neurons in the inner retina that are part of the dim light rod pathway are not due to cell death, but the mechanism is unknown. Dopamine is released by dopaminergic amacrine cells to allow the retina to adapt to increasing background light levels. Diabetic retinas have low dopamine levels and supplementation of dopamine can reduce inner retinal deficits in diabetes. As experts in rod pathway signaling, Dr. Eggers’ laboratory team will determine if this pathway is specifically vulnerable to diabetic damage and identify the mechanism of dysfunction to develop targeted therapeutics to prevent the neuronal progression of vision loss.

In 2023, Dr. Eggers proposed to continue studying the isolated retinal ERG in diabetes with dopamine modulators and different light intensities to find some global dopamine changes. Her lab also plans to continue their experiments to measure dopamine release in the diabetic retina.

Specific Aims: 1: Determine if diabetes induced reduction in dopamine levels reduces dopamine receptor sensitivity of the inner retinal rod pathway. We hypothesize that reduced dopamine levels in early diabetes change the sensitivity of neuron’s responses to dopamine. We will measure the responses of individual retinal neurons to light and determine how dopamine receptor agonists modulate them.

2: Determine if diabetes reduces the release and retinal function of dopamine in light adaptation. We hypothesize that lowered diabetic retinal dopamine reduces retinal dopamine release and adaptation to increased light levels. We will measure neuron and dopamine release in response to increasing background light levels.

Progress in 2022

Dr. Eggers found that dopamine receptor 1 and 4 modulation of the entire retina, using the isolated retinal electroretinogram (ERG), is reduced but still present after 6 weeks of diabetes. This fits with earlier results that Dopamine 4 receptor modulation of ganglion cells is reduced, but still present after six weeks of diabetes. This validates the isolated retinal ERG as a screening tool to look at retinal modulators without requiring many retinas and individual neuron recordings. Dr. Eggers plans to submit this work as an abstract for ARVO 2023.

Progress in 2021

Dr. Eggers found that one type of dopamine receptor has reduced capability to modulate responses to light in the diabetic retina, but the expression levels of this receptor did not change. This suggests that dopamine signaling, and not just dopamine levels, are affected in early diabetes. However, the continued receptor presence and ability to modulate signaling, albeit at a reduced level, suggest that dopamine supplementation could be a viable treatment option.