Retinal ganglion cell (RGC) death occurs after optic nerve injury due to acute trauma or chronic degenerative conditions such as optic neuropathies (e.g., glaucoma). Currently, there are no effective therapies to prevent permanent vision loss resulting from RGC death, underlining the need for research on the pathogenesis of RGC disorders. Modeling human RGC/optic nerve diseases in non-human primates is ideal because of their similarity to humans, but has practical limitations including high cost and ethical considerations. In addition, many retinal degenerative disorders are age-related making the study in primate models prohibitively slow. For these reasons, mice and rats are commonly used to model RGC injuries. However, as nocturnal mammals, these rodents have retinal structures that differ from primates - possessing less than one-tenth of the RGCs found in the primate retina. Here we report the diurnal thirteen-lined ground squirrel (TLGS) as an alternative model. Compared to other rodent models, the number and distribution of RGCs in the TLGS retina are closer to primates. The TLGS retina possesses ~600,000 RGCs with the highest density along the equatorial retina matching the location of the highest cone density (visual streak). TLGS and primate retinas also share a similar interlocking pattern between RGC axons and astrocyte processes in the retina nerve fiber layer (RNFL). In addition, using TLGS we establish a new partial optic nerve injury model that precisely controls the extent of injury while sparing a portion of the retina as an ideal internal control for investigating the pathophysiology of axon degeneration and RGC death. Moreover, in vivo optical coherence tomography (OCT) imaging and ex vivo microscopic examinations of the retina in optic nerve injured TLGS confirm RGC loss precedes proximal axon degeneration, recapitulating human pathology. Thus, the TLGS retina is an excellent model, for translational research in neurodegeneration and therapeutic neuroprotection.
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Data availability statement
The data that supports the findings of this study are available within the article and its supplementary material. Raw or additional data are available from the corresponding author upon reasonable request.
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We would like to thank the Animal Care team, especially Dr. Ginger Tansey, Amber Lopez, Denise Parker, Irina Bunea, and Kristi Creel for taking care of our TLGS colony. We also express our appreciation to Dr. Haohua Quiao and Dr. Yichao Li of the NIH Visual Function Core for providing training in the use of the SD-OCT. We would also like to thank Dr. David Pow (University of Queensland, Brisbane, Australia) for providing the glycine antibody. We also would like to thank Dr. Tao Sun (National Institute of Neurological Disorders and Stroke) for providing postmortem rat specimens, and Dr. Lauren Brinster (Diagnostic and research services branch-NIH), Dr. Mark A. Eldridge (National Institute of Mental Health) and, Dr. Julie Mattison and Dr. Kielee Jennings (Nonhuman Primate Core of the National Institute on Aging) for providing postmortem monkey specimens.
This research was supported by Intramural Research Program of the National Eye Institute, National Institutes of Health and, by the Office of the Assistant Secretary of Defense for Health Affairs and the Defense Health Agency J9, Research and Development Directorate, through the Vision Research Program under Award No. CDMRPL-18-0-VR180205. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.
Ethics approval and consent to participate
Each species was treated and maintained according to their unique protocols (mouse, ASP#606; TLGS: ASP#595) approved by the National Institutes of Health guidelines for Animal Care and Use Committee in research and by the Ethical and Animal Studies Committee of the National Eye Institute. All animal studies conformed to the Statement for the Use of Animals in Ophthalmic and Vision research of the Association for Research in Vision and Ophthalmology (ARVO). In conducting this research, we adhered to the laws of the United States and regulations of the US Department of Agriculture.
The authors declare no competing interests.
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Xiao, X., Zhao, T., Miyagishima, K.J. et al. Establishing the ground squirrel as a superb model for retinal ganglion cell disorders and optic neuropathies. Lab Invest (2021). https://doi.org/10.1038/s41374-021-00637-y