Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs): Promising Biomarkers for Neurodegenerative Diseases

The treatment of neurodegenerative conditions like Glaucoma, Alzheimer’s, and Parkinson’s disease can be improved if they are recognized and diagnosed very early, ideally before severe symptoms are noticeable. Having biomarkers for these disorders could significantly improve early detection and therefore health outcomes for many people. Previous studies have suggested that a decline or dysfunction in the number of special retinal cells, known as intrinsically photosensitive retinal ganglion cells (ipRGCs), is associated with the onset of many of these diseases. This offers the opportunity to use the decline in ipRGC frequency and function as an early biomarker. However, normal aging may also influence ipRGCs, and a difference in ipRGC stability has been reported between males and females. Using ipRGCs as a biomarker therefore requires careful description of their normal state during aging, to serve as a baseline against which their state during disease can be compared.

In a recent study, Matynia et al. at the University of Houston College of Optometry (UHCO) and colleagues at the University of California, Los Angeles (UCLA), analyzed ipRGC functions and morphology in healthy mice across the mature-adult (6 months) to old-adult (12 months) lifespan. This is the relevant age range where degenerative disease symptoms would be expected to emerge. They found that ipRGC number, morphology, and ipRGC-mediated behavior in these mice was consistent and stable, both across the age groups, and across male and female mice. This stability in healthy mice confirms the viability of ipRGCs as potential biomarkers for degenerative disease.

ipRGC Roles and the Impact of Neuronal Health

ipRGCs are one of three types of photoreceptors in the mammalian retina. In contrast to the “standard” photoreceptors, the rods and the cones, ipRGCs contain the photopigment melanopsin, which makes them particularly responsive to blue light. Their role is to detect overall ambient light levels. Specifically, the M1 subtype supports such non-image forming functions such as regulating the circadian rhythm (photoentrainment), pupillary light reflex, and sleep-wake cycles, by controlling melatonin levels. Additionally, the M4 subtype supports image-forming vision, specifically supporting contrast sensitivity.

Prior research showed that ipRGC density remains stable in healthy human adults until around age 70, after which a significant decline occurs, impacting sleep and circadian rhythm regulation in the elderly. A premature decline has been linked to various neurodegenerative diseases, such as Alzheimer’s, Huntington’s, and Parkinson’s disease, glaucoma, or diabetes. Some of these diseases exhibit sex-specific differences in onset. For example, early-onset Alzheimer’s is particularly prevalent in women, whereas early Parkinson’s is more common in men. These differences complicate diagnostics, highlighting the need for early-stage markers.

The stability of ipRGCs during normal aging – at least until about 70 years – suggests that their decline may serve as an early indicator for a multitude of different neurodegenerative diseases with otherwise diverse symptoms. This would include the possibility to identify sex-specific disease onset differences. However, other studies have raised questions about the consistency of ipRGC function and morphology over time.

Investigating ipRGC Functions and Morphological Stability in Aging Mice

The UHCO and UCLA research team investigated the function of ipRGCs by conducting a series of tests on male and female mice aged 6 and 12 months. All tests showed comparable results for female and male mice, indicating no sex-related differences in ipRGCs and proving sex-independent stability.

First, they examined light avoidance, where the animals can choose to spend time either in a bright environment or move to a darkened area in the experimental arena. Mice normally tend to prefer the dark region when the environment is new. To avoid this anxiety-related dark preference, mice were extensively habituated to the testing environment such that their preference for the dark region was significantly reduced. Dilation of the pupil, which results in stronger activation of ipRGCs, increased light avoidance. Mice lacking ipRGCs, in contrast, spent almost equal time in the bright and dark environments, with pupil dilation showing no effect. Taken together, these results suggest that the light-avoidance test can give an indication of ipRGC function.

The older animals (12 months) showed a small increase in light avoidance with and without pupil dilation. Interestingly, the mice lacking ipRGCs also showed a small increase in light avoidance with age. This suggests that the increase of light avoidance with age may at least partly be attributed to pathways involving standard photoreceptors.

The pupillary light reflex, which controls pupil constriction in response to light, was also investigated. Consistent with the known role of ipRGCs, mice lacking ipRGCs had significantly reduced (but not completely absent) pupil response. In addition, there were no significant differences between the two age groups in any of the animals.

Another readout for ipRGC function can be contrast sensitivity, as the M4 class of ipRGCs has been implicated to support this function. Contrast sensitivity, as well as visual acuity, were tested using Striatech’s OptoDrum. The results showed that contrast sensitivity and visual acuity remained stable in both six- and twelve-month-old mice. This indicates there was no age-related decline in these visual functions for healthy mice between 6 and 12 months.

The researchers also compared changes in ipRGC cell morphology over time, focusing on soma size, dendritic network complexity, and overall cell density. They used anti-melanopsin antibodies to identify the M1 class of ipRGCs in mouse retinas. The findings concluded that M1 ipRGCs maintained stable morphology in both age groups.

Significance of IpRGCs as Biomarkers for Early Detection of Neurodegeneration

The study by Matynia et al. confirmed that both the function and morphology of ipRGCs remain stable throughout adulthood in mice, showing no sex differences. This stability highlights their potential as biomarkers for neural degradation. A decrease in ipRGC function, such as reduced light aversion, could serve as an early indicator of neurodegenerative diseases. Similarly, contrast sensitivity does not decline with age, suggesting that its potential prognostic role could be confirmed upon further investigation.

While ipRGC loss is common in neurodegenerative diseases, the authors point out that ipRGC decline may vary and depend on the specific disease. Ocular phenotypes can be quite complex, with genetics of the disease interacting with other factors. They urge that additional research is needed to gain a deeper understanding of the specific connections between ipRGCs and individual pathologies, as well as the connection with other photoreceptors.

Overall, ipRGCs show promise as resilient biomarkers: when their function deteriorates, this may serve as early warning signs of disease. Further research, including studies on older mice and specific models of neurodegenerative disease, is needed to validate their clinical applicability.

For more insights, join our upcoming Journal Club with Anna Matynia discussing the implications of Alzheimer’s disease on visual function in mice.

Blog author:
Emilia Kawecka, University of Tübingen, Student Assistant at Striatech GmbH

Original paper:
Matynia A, Recio BS, Myers Z, Parikh S, Goit RK, Brecha NC, Pérez de Sevilla Müller L. Preservation of Intrinsically Photosensitive Retinal Ganglion Cells (ipRGCs) in Late Adult Mice: Implications as a Potential Biomarker for Early Onset Ocular Degenerative Diseases. Invest Ophthalmol Vis Sci. 2024 Jan 2;65(1):28. doi: 10.1167/iovs.65.1.28.

Source material ipRGCs in neurodegerative diseases:
Adhikari, P. et al. (2016): Quadrant Field Pupillometry Detects Melanopsin Dysfunction in Glaucoma Suspects and Early Glaucoma. In: Sci Rep, 6. Jg., S. 33373. URL: https://www.ncbi.nlm.nih.gov/pubmed/27622679

Breen, D. P. et al. (2014): Sleep and circadian rhythm regulation in early Parkinson disease. In: JAMA Neurol, 71. Jg. (5), S. 589-595. URL: https://www.ncbi.nlm.nih.gov/pubmed/24687146

De Lazzari, F. et al. (2018): Circadian Rhythm Abnormalities in Parkinson’s Disease from Humans to Flies and Back. In: Int J Mol Sci, 19. Jg. (12). URL: https://www.ncbi.nlm.nih.gov/pubmed/30563246

Gao, J./Provencio, I./Liu, X. (2022): Intrinsically photosensitive retinal ganglion cells in glaucoma. In: Front Cell Neurosci, 16. Jg., S. 992747. URL: https://www.ncbi.nlm.nih.gov/pubmed/36212698

Gros, P./Videnovic, A. (2020): Overview of Sleep and Circadian Rhythm Disorders in Parkinson Disease. In: Clin Geriatr Med, 36. Jg. (1), S. 119-130. URL: https://www.ncbi.nlm.nih.gov/pubmed/31733692

Hinton, D. R. et al. (1986): Optic-nerve degeneration in Alzheimer’s disease. In: N Engl J Med, 315. Jg. (8), S. 485-487. URL: https://www.ncbi.nlm.nih.gov/pubmed/3736630

Jean-Louis, G. et al. (2008): Circadian rhythm dysfunction in glaucoma: A hypothesis. In: J Circadian Rhythms, 6. Jg., S. 1. URL: https://www.ncbi.nlm.nih.gov/pubmed/18186932

Musiek, E. S./Holtzman, D. M. (2016): Mechanisms linking circadian clocks, sleep, and neurodegeneration. In: Science, 354. Jg. (6315), S. 1004-1008. URL: https://www.ncbi.nlm.nih.gov/pubmed/27885006

Toljan, K./Homolak, J. (2021): Circadian changes in Alzheimer’s disease: Neurobiology, clinical problems, and therapeutic opportunities. In: Handb Clin Neurol, 179. Jg., S. 285-300. URL: https://www.ncbi.nlm.nih.gov/pubmed/34225969

Zuzuarregui, J. R. P./During, E. H. (2020): Sleep Issues in Parkinson’s Disease and Their Management. In: Neurotherapeutics, 17. Jg. (4), S. 1480-1494. URL: https://www.ncbi.nlm.nih.gov/pubmed/33029723