Investigators Discover a New Subset of Interneurons within the Retina

Investigators have discovered a new subset of interneurons within the retina. This discovery, as reported in a study by Northwestern Medicine published in Nature Communications, enhances the eye's ability to perceive and recognize objects in both well-lit and low-light conditions.

The findings challenge previously held beliefs regarding the internal mechanisms of the eye and carry significant implications for guiding future neuroscience research. The study's senior author, Yongling Zhu, Ph.D., an assistant professor of Ophthalmology and Neuroscience, underscores the broader impact of these findings.

In the mammalian eye, the retina serves as the initial converter of light into electrical signals, subsequently relayed to the brain by the optic nerve to enable vision. These electrical signals undergo processing within a densely interconnected synaptic layer in the retina, which is divided into two distinct halves before they are transmitted to the brain.

For years, it was widely accepted in the scientific community that neurons in one half of the synaptic layer respond when light is switched on, while those in the other half respond when the light is turned off. However, Zhu's research team has recently unveiled a previously unknown subtype of interneurons known as amacrine cells, which can generate an "off" signal even when located in the "on" half of the synaptic layer.

"The 'on' and 'off' division is considered to be the fundamental organizing plan of the retina; however, our study has discovered an exception to this organization plan,” Zhu remarked.

Amacrine cells function as inhibitory interneurons in the retina, playing the role of traffic controllers for visual signals. These signals travel from the light-detecting photoreceptors to the retina's ganglion cells, which subsequently transmit electrical signals to the brain. Recent advancements in genetic technologies have made it feasible to systematically study the various subtypes of amacrine cells.

"Each subtype possesses a unique shape and genetic profile, and they form connections with other neurons in distinct and specialized ways. Studying these cells has been exceptionally challenging, mainly due to the absence of genetic tools that would allow for the labeling or manipulation of specific subtypes," Zhu said.

In the present study, Zhu's team used a novel genetic approach known as an "intersectional strategy." This method entails the labeling and isolation of amacrine cell subtypes in mouse retinas that express two distinct proteins. This approach allows for the identification of more specific cell types than when using only one protein for labeling.

To the investigators' astonishment, they uncovered a previously unrecognized subtype of amacrine cell. This subtype forms synapses in the "on" half of the synaptic layer but functions similarly to the cells typically located in the "off" half.

Using fluorescent sensors to monitor the cell's actions, alongside genetic and pharmacological interventions, the researchers additionally observed that these cells employ an inhibitory glutamate receptor known as mGluR8 rather than the excitatory glutamate receptor AMPA, which is expressed by all other amacrine cells, for receiving electrical signals.

In this manner, these newly discovered amacrine cells serve as a switch, converting incoming excitatory signals into inhibitory ones before relaying them to downstream neurons and, ultimately, to the brain, as described by Zhu.

"This particular amacrine cell is not only a new kind of neuron, but it also exhibits a new way of conveying information from one half of the retina layer to the other. This information transfer increases the sensitivity of retinal neurons to detect objects in the dark and enhances their ability to distinguish different motions in the light," Zhu said.

Moving ahead, Zhu articulated her team's objective, which is to enhance their intersectional strategy to attain single-cell type labeling and, subsequently, investigate the influence of this amacrine subtype on various visual pathways and downstream neurons.

"There are about 60 different types of amacrine cells. They're all very specialized, all have a different function, all are very difficult to access, and the technique that we have developed can be used on each one, one at a time… Now we have a way, a really robust way of going from one to the next," said Steven DeVries, MD, Ph.D., the David Shoch, MD, Ph.D., Professor of Ophthalmology and a co-author of the study.

Reference

Andrew Jo et al, A sign-inverted receptive field of inhibitory interneurons provides a pathway for ON-OFF interactions in the retina, Nature Communications (2023). DOI: 10.1038/s41467-023-41638-3