The Healthy and Diseased Retina Seen through Neuron-Glia Interactions

Abstract

The retina is the sensory tissue responsible for the first stages of visual processing, with a conserved anatomy and functional architecture among vertebrates. To date, retinal eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, glaucoma, and others, affect nearly 170 million people worldwide, resulting in vision loss and blindness. To tackle retinal disorders, the developing retina has been explored as a versatile model to study intercellular signaling, as it presents a broad neurochemical repertoire that has been approached in the last decades in terms of signaling and diseases. Retina, dissociated and arranged as typical cultures, as mixed or neuron- and glia-enriched, and/or organized as neurospheres and/or as organoids, are valuable to understand both neuronal and glial compartments, which have contributed to revealing roles and mechanisms between transmitter systems as well as antioxidants, trophic factors, and extracellular matrix proteins. Overall, contributions in understanding neurogenesis, tissue development, differentiation, connectivity, plasticity, and cell death are widely described. A complete access to the genome of several vertebrates, as well as the recent transcriptome at the single cell level at different stages of development, also anticipates future advances in providing cues to target blinding diseases or retinal dysfunctions.

Keywords: disease; glia; neuron; retina; signaling.

Figure 1

Comparative analysis of the vertebrate retina, selective mediators, and glutamate receptor expression across species. A comprehensive illustration of the retinal structure, neurotransmitter distribution, and glutamate receptor subunit expression across various species. The left side of the image presents a detailed cross-sectional view of the retina, delineating its layered architecture and the cellular components within each layer. The layers are sequentially labeled from the outermost to the innermost as follows: choroid, Bruch’s membrane, pigment epithelium (PE), photoreceptor outer segments (POS), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer (IPL), ganglion cell layer (GCL), and nerve fiber layer (NFL). The direction of light entering the retina is indicated by yellow arrows at the bottom, pointing towards the nerve fiber layer. Cell types within the retina are represented by distinct symbols: cones and rods (photoreceptors), Müller glia, horizontal cells, bipolar cells, amacrine cells, and ganglion cells. These symbols are color-coded and positioned to reflect their location within the retinal layers, illustrating the complex interplay of the cells involved in visual processing. The right side of the image features a chart displaying the molecular structures of various neurotransmitters, including glutamate, ATP, D-serine, GABA, dopamine, acetylcholine, and serotonin. It should be noted that acetylcholine and GABA were also present in displaced amacrine cells in the GCL. These neurotransmitters play pivotal roles in retinal signal transduction and are essential for the proper functioning of the visual system. Below the transmitter chart, a key indicates the expression of different glutamate receptor subunits (NR1, NR2A, NR2B, NR2C, GluR5, GluR6/7, GluR6, GluR7, KA1, and KA2) across six species: goldfish (G), rat (R), rabbit (Rb), monkey (M), mouse (Ms), and cat (C). Each species is represented with an icon and a corresponding initial, providing a comparative view of glutamate receptor diversity and its potential impact on visual processing across different vertebrates. Created with BioRender.com—agreement number VL26BHMCYU.

Figure 2

Regulatory pathways involved in retinal stress responses and diabetic retinopathy progression. Cellular mechanisms of the retinal response to stress under constitutive conditions, oxidative stress, and in the context of high glucose (HG) or diabetic retinopathy (DR). The left panel depicts the constitutive degradation pathway of the transcription factor Nrf2, which is bound by the Kelch-like ECH-associated protein 1 (Keap1) and targeted for ubiquitination and subsequent proteasomal degradation under normal conditions. The central panel shows the response to a light to mild oxidative stress, where reactive oxygen species (ROS) or electrophiles modify cysteine residues on Keap1, leading to the release of Nrf2. Nrf2 can also be phosphorylated by protein kinases, which promotes its translocation into the nucleus. Once in the nucleus, Nrf2 binds to antioxidant response elements (AREs) in the DNA, leading to the expression of proteins of the antioxidant response. The right panel focuses on the molecular pathways involved in diabetic retinopathy, a condition characterized by increased glucose levels that lead to retinal damage. Here, the diagram outlines the interplay between ROS/electrophiles and various signaling molecules, including REDD1, PP2A, PTEN, and PHLPP2, all of them are increased by HG/DR, inhibiting AKT. Activated AKT (p-AKT) phosphorylates and inactivates GSK3β, which, in turn, affects Nrf2 activity. Additionally, the diagram indicates the involvement of ERK, AMPK, and SIRT1, which positively regulates Nrf2, but are all decreased in HG/DR, inhibiting the Nrf2-activated antioxidant response. Created with BioRender.com (agreement number: TI268KUA0F).