2 min readOrigin of Neuromodulator in the Retina Pinpointed

Evanston, IL — A single cell type in the inner retina controls the release of nitric oxide, a neuromodulator that impacts synaptic transmission and regulates blood vessel dilation, according to a Northwestern Medicine study published in Neuron.

Nitric oxide’s (NO) role in blood vessel regulation means those cells, a specific kind of amacrine cell called nNOS-2, could be used to help diagnose blood vessel disorders or even as targets for future therapies, according to Dr. Gregory Schwartz, assistant professor of Ophthalmology and senior author of the study.

“Neurons communicate with blood vessels, directing blood flow in a process called neurovascular coupling,” said Schwartz, who is also a professor of Physiology. “Nitric oxide assists in that process, and nitric oxide-releasing cells may be important to that process in both the retina and in the rest of the body.”

While neurotransmitters are the main mechanism by which neurons “talk” to one another, neuromodulators affect neuronal communication in a variety of ways, providing a finer level of control.

In the inner retina, gaseous NO regulates blood vessel dilation when released, diffusing across cell membranes. This is an important function for the eye; different lighting conditions require blood flow to different areas of the eye, and NO is believed to have some effect on this process. However, little had been previously known about the neurons that release NO.

Working in retinal models, Schwartz and his collaborators tagged NO’s precursor enzyme — nitric oxide synthase (NOS) — with a fluorescent tag, and searched for cells that were producing this synthase. They discovered that the nNOS-2 amacrine cell subtype was responsible for the lion’s share of NO production in the inner retina.

“This is a beautiful way to regulate nitric oxide, because it’s nonspecific and it impacts all the vasculature that it contacts,” said Dr. Jason Jacoby, postdoctoral fellow in the Schwartz laboratory and first author of the study. “These cells work together through network connectivity to create a ’cloud’ of NO that has far-reaching impact.”

This discovery could have implications for diseases involving blood flow, such as diabetic neuropathy, a complication of diabetes that results in damage to retinal blood vessels. Because the retina has such high blood flow requirements, clinicians might be able to detect dysfunction in nitric oxide-releasing amacrine cells before there is ever actual damage to the vessels.

The study authors are currently collaborating with Dr. Amani Fawzi, the Cyrus Tang and Lee Jampol Professor of Ophthalmology, trying to establish a link between the light stimulus conditions that activate the amacrine cells and the corresponding changes in vasculature. Patients with early retinopathy may have a blunted response that could be measured on optical coherence tomography angiography, according to Schwartz.

“It could be an early warning sign, before blood vessels collapse or any real structural changes,” Schwartz said. “You might be able to diagnose diabetic retinopathy years earlier than you would be able to otherwise.”

While this study was performed in laboratory models of the retina, the authors believe that NO-releasing neurons could have a significant impact on neurovascular coupling throughout the body, and may be attractive therapeutic targets in other vascular conditions including stroke.

“If we can understand more about the basic mechanisms that are governing how NO is released, then we might be able to change the dynamics of blood flow in the context of injury,” said Zachary Jessen, a second-year student in the Medical Scientist Training Program and co-author of the study. “We could potentially intervene to prevent damage from occurring.”

Article adapted from a Northwestern University news release.

Publication: A Self-Regulating Gap Junction Network of Amacrine Cells Controls Nitric Oxide Release in the Retina. Jason Jacoby et al.Neuron (2018): Click here to view.

Amacrine Cells, Neuromodulator, nitric oxide, Retina

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