Neurodegeneration, Neuroprotection and Regeneration in the Zebrafish Retina

Abstract

Neurodegenerative retinal diseases, such as glaucoma and diabetic retinopathy, involve a gradual loss of neurons in the retina as the disease progresses. Central nervous system neurons are not able to regenerate in mammals, therefore, an often sought after course of treatment for neuronal loss follows a neuroprotective or regenerative strategy. Neuroprotection is the process of preserving the structure and function of the neurons that have survived a harmful insult; while regenerative approaches aim to replace or rewire the neurons and synaptic connections that were lost, or induce regrowth of damaged axons or dendrites. In order to test the neuroprotective effectiveness or the regenerative capacity of a particular agent, a robust experimental model of retinal neuronal damage is essential. Zebrafish are being used more often in this type of study because their eye structure and development is well-conserved between zebrafish and mammals. Zebrafish are robust genetic tools and are relatively inexpensive to maintain. The large array of functional and behavioral tests available in zebrafish makes them an attractive model for neuroprotection studies. Some common insults used to model retinal disease and study neuroprotection in zebrafish include intense light, chemical toxicity and mechanical damage. This review covers the existing retinal neuroprotection and regeneration literature in the zebrafish and highlights their potential for future studies.

Keywords: chemical toxicity; diet; light-induced retinal degeneration; mechanical damage; optic nerve; oxidative stress; photoreceptors; retinal damage; retinal ganglion cells; retinal stab.

Figure 1

Neurons and glia in the zebrafish retina. Confocal image showing examples of neurons and glia (green) in the zebrafish retina: (A) anti-Zpr1 labels the double-cone (DC) photoreceptors; (B) anti-PKCα labels the large Mb-1 bipolar cells and all ON-bipolar cells; (C) anti-islet1/2 labels the RGCs, (although a few other cell types are labelled non-specifically in the INL); (D) transgenic Lhx1A zebrafish have GFP-labelled horizontal cells in the OPL; (E) anti-tyrosine hydroxylase labels the amacrine cells in the INL; (F) anti-glutamine synthetase to label the Müller glia. Nuclei are also labeled (blue). Other glial cells that are present in the zebrafish retina include microglia and astrocytes (not labeled). Abbreviations: PRs, photoreceptors; BPCs, Bipolar cells; RGCs, retinal ganglion cells; HC, Horizontal cells; AC, Amacrine cells; OS, outer segments; IS, inner segments; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. Scale bar = 20 µm.

Figure 2

Types of photoreceptors in the zebrafish retina. Illustration showing the different types of photoreceptors in the zebrafish outer retina, along with the location of their outer segment (black arrowhead), ellipsoid (black arrow), myoid (white arrow), nuclei (star), and terminals in the OPL. Confocal image shows anti-Zpr1 (green) labelling of DC photoreceptors and nuclei (blue) in the zebrafish retina. Abbreviations: SSC, short single cones (SSC); LSC, long single cones; DC, double cones; ROS, rod outer segments; dCOS, double cone outer segments; LCIS, long cone inner segment sublayer; cONL, cone outer nuclear layer; olm, outer limiting membrane; rONL rod outer nuclear layer; OPL, outer plexiform layer, RPE, retinal pigment epithelium; OS, outer segment; ONL, outer nuclear layer; INL, inner nuclear layer. Figure adapted from [64].