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Differential susceptibility of retinal ganglion cell subtypes against neurodegenerative diseases

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Abstract

Retinal ganglion cells (RGCs) are essential to propagate external visual information from the retina to the brain. Death of RGCs is speculated to be closely correlated with blinding retinal diseases, such as glaucoma and traumatic optic neuropathy (TON). Emerging innovative technologies have helped refine and standardize the classification of RGCs; at present, they are classified into more than 40 subpopulations in mammals. These RGC subtypes are identified by a combination of anatomical morphologies, electrophysiological functions, and genetic profiles. Increasing evidence suggests that neurodegenerative diseases do not collectively affect the RGCs. In fact, which RGC subtype exhibits the strongest or weakest susceptibility is hotly debated. Although a consensus has not yet been reached, it is certain that assorted RGCs display differential susceptibility against irreversible degeneration. Interestingly, a single RGC subtype can exhibit various vulnerabilities to optic nerve damage in diverse injury models. Thus, elucidating how susceptible RGC subtypes are to various injuries can protect vulnerable RGCs from damage and improve the possibility of preventing and treating visual impairment caused by neurodegenerative diseases. In this review, we summarize in detail the progress and status quo of research on the type-specific susceptibility of RGCs and point out current limitations and the possible directions for future research in this field.

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References

  1. Jin ZB, Gao ML, Deng WL et al (2019) Stemming retinal regeneration with pluripotent stem cells. Prog Retin Eye Res 69:38–56. https://doi.org/10.1016/j.preteyeres.2018.11.003

    Article  CAS  PubMed  Google Scholar 

  2. Park HL, Kim JH, Park CK (2018) Different contributions of autophagy to retinal ganglion cell death in the diabetic and glaucomatous retinas. Sci Rep 8:13321. https://doi.org/10.1038/s41598-018-30165-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Liu WW, Margeta MA (2019) Imaging retinal ganglion cell death and dysfunction in glaucoma. Int Ophthalmol Clin 59:41–54. https://doi.org/10.1097/iio.0000000000000285

    Article  PubMed  Google Scholar 

  4. Yu DY, Cringle SJ, Balaratnasingam C et al (2013) Retinal ganglion cells: energetics, compartmentation, axonal transport, cytoskeletons and vulnerability. Prog Retin Eye Res 36:217–246. https://doi.org/10.1016/j.preteyeres.2013.07.001

    Article  CAS  PubMed  Google Scholar 

  5. Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A (2012) The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 31:152–181. https://doi.org/10.1016/j.preteyeres.2011.11.002

    Article  CAS  PubMed  Google Scholar 

  6. Ventura LM, Porciatti V (2005) Restoration of retinal ganglion cell function in early glaucoma after intraocular pressure reduction: a pilot study. Ophthalmology 112:20–27. https://doi.org/10.1016/j.ophtha.2004.09.002

    Article  PubMed  Google Scholar 

  7. Porciatti V, Ventura LM (2012) Retinal ganglion cell functional plasticity and optic neuropathy: a comprehensive model. J Neuroophthalmol 32:354–358. https://doi.org/10.1097/WNO.0b013e3182745600

    Article  PubMed  PubMed Central  Google Scholar 

  8. Crowston JG, Fahy ET, Fry L et al (2017) Targeting retinal ganglion cell recovery Eye (Lond) 31:196–198. https://doi.org/10.1038/eye.2016.281

    Article  CAS  Google Scholar 

  9. Dhande OS, Stafford BK, Lim JA, Huberman AD (2015) Contributions of retinal ganglion cells to subcortical visual processing and behaviors. Annu Rev Vis Sci 1:291–328. https://doi.org/10.1146/annurev-vision-082114-035502

    Article  PubMed  Google Scholar 

  10. Sanes JR, Masland RH (2015) The types of retinal ganglion cells: current status and implications for neuronal classification. Annu Rev Neurosci 38:221–246. https://doi.org/10.1146/annurev-neuro-071714-034120

    Article  CAS  PubMed  Google Scholar 

  11. Kim US, Mahroo OA, Mollon JD, Yu-Wai-Man P (2021) Retinal ganglion cells-diversity of cell types and clinical relevance. Front Neurol 12:661938. https://doi.org/10.3389/fneur.2021.661938

    Article  PubMed  PubMed Central  Google Scholar 

  12. Rheaume BA, Jereen A, Bolisetty M et al (2018) Single cell transcriptome profiling of retinal ganglion cells identifies cellular subtypes. Nat Commun 9:2759. https://doi.org/10.1038/s41467-018-05134-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Baden T, Berens P, Franke K et al (2016) The functional diversity of retinal ganglion cells in the mouse. Nature 529:345–350. https://doi.org/10.1038/nature16468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Coombs J, van der List D, Wang GY, Chalupa LM (2006) Morphological properties of mouse retinal ganglion cells. Neuroscience 140:123–136. https://doi.org/10.1016/j.neuroscience.2006.02.079

    Article  CAS  PubMed  Google Scholar 

  15. Sümbül U, Song S, McCulloch K et al (2014) A genetic and computational approach to structurally classify neuronal types. Nat Commun 5:3512. https://doi.org/10.1038/ncomms4512

    Article  CAS  PubMed  Google Scholar 

  16. Martersteck EM, Hirokawa KE, Evarts M et al (2017) Diverse central projection patterns of retinal ganglion cells. Cell Rep 18:2058–2072. https://doi.org/10.1016/j.celrep.2017.01.075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Roy S, Jun NY, Davis EL, Pearson J, Field GD (2021) Inter-mosaic coordination of retinal receptive fields. Nature 592:409–413. https://doi.org/10.1038/s41586-021-03317-5

    Article  CAS  PubMed  Google Scholar 

  18. Crook JD, Peterson BB, Packer OS et al (2008) Y-cell receptive field and collicular projection of parasol ganglion cells in macaque monkey retina. J Neurosci 28:11277–11291. https://doi.org/10.1523/jneurosci.2982-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tran NM, Shekhar K, Whitney IE et al (2019) Single-cell profiles of retinal ganglion cells differing in resilience to injury reveal neuroprotective Genes. Neuron 104(1039–1055):e12. https://doi.org/10.1016/j.neuron.2019.11.006

    Article  CAS  Google Scholar 

  20. Kölsch Y, Hahn J, Sappington A et al (2021) Molecular classification of zebrafish retinal ganglion cells links genes to cell types to behavior. Neuron 109:645-662.e9. https://doi.org/10.1016/j.neuron.2020.12.003

    Article  CAS  PubMed  Google Scholar 

  21. Bae JA, Mu S, Kim JS et al (2018) Digital museum of retinal ganglion cells with dense anatomy and physiology. Cell 173:1293-1306.e19. https://doi.org/10.1016/j.cell.2018.04.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Glovinsky Y, Quigley HA, Dunkelberger GR (1991) Retinal ganglion cell loss is size dependent in experimental glaucoma. Invest Ophthalmol Vis Sci 32:484–491

    CAS  PubMed  Google Scholar 

  23. Shou T, Liu J, Wang W, Zhou Y, Zhao K (2003) Differential dendritic shrinkage of alpha and beta retinal ganglion cells in cats with chronic glaucoma. Invest Ophthalmol Vis Sci 44:3005–3010. https://doi.org/10.1167/iovs.02-0620

    Article  PubMed  Google Scholar 

  24. Milla-Navarro S, Diaz-Tahoces A, Ortuño-Lizarán I et al (2021) Visual disfunction due to the selective effect of glutamate agonists on retinal cells. Int J Mol Sci 22:44–66. https://doi.org/10.3390/ijms22126245

    Article  Google Scholar 

  25. Yang N, Young BK, Wang P, Tian N (2020) The susceptibility of retinal ganglion cells to optic nerve injury is type specific. Cells 9:677. https://doi.org/10.3390/cells9030677

    Article  CAS  PubMed Central  Google Scholar 

  26. VanderWall KB, Lu B, Alfaro JS et al (2020) Differential susceptibility of retinal ganglion cell subtypes in acute and chronic models of injury and disease. Sci Rep 10:17359. https://doi.org/10.1038/s41598-020-71460-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vidal-Villegas B, Di Pierdomenico J, Miralles de Imperial-Ollero JA et al (2019) Melanopsin(+)RGCs are fully resistant to NMDA-induced excitotoxicity. Int J Mol Sci 20:3012. https://doi.org/10.3390/ijms20123012

    Article  CAS  PubMed Central  Google Scholar 

  28. Honda S, Namekata K, Kimura A et al (2019) Survival of alpha and intrinsically photosensitive retinal ganglion cells in NMDA-induced neurotoxicity and a mouse model of normal tension glaucoma. Invest Ophthalmol Vis Sci 60:3696–3707. https://doi.org/10.1167/iovs.19-27145

    Article  CAS  PubMed  Google Scholar 

  29. Daniel S, Meyer KJ, Clark AF, Anderson MG, McDowell CM (2019) Effect of ocular hypertension on the pattern of retinal ganglion cell subtype loss in a mouse model of early-onset glaucoma. Exp Eye Res 185:107703. https://doi.org/10.1016/j.exer.2019.107703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Christensen I, Lu B, Yang N et al (2019) The susceptibility of retinal ganglion cells to glutamatergic excitotoxicity is type-specific. Front Neurosci 13:219. https://doi.org/10.3389/fnins.2019.00219

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wang S, Gu D, Zhang P et al (2018) Melanopsin-expressing retinal ganglion cells are relatively resistant to excitotoxicity induced by N-methyl-d-aspartate. Neurosci Lett 662:368–373. https://doi.org/10.1016/j.neulet.2017.10.055

    Article  CAS  PubMed  Google Scholar 

  32. Mayer C, Bruehl C, Salt EL et al (2018) Selective vulnerability of αOFF retinal ganglion cells during onset of autoimmune optic neuritis. Neuroscience 393:258–272. https://doi.org/10.1016/j.neuroscience.2018.07.040

    Article  CAS  PubMed  Google Scholar 

  33. Daniel S, Clark AF, McDowell CM (2018) Subtype-specific response of retinal ganglion cells to optic nerve crush. Cell Death Discov 4:7. https://doi.org/10.1038/s41420-018-0069-y

    Article  CAS  PubMed  Google Scholar 

  34. Puyang Z, Gong HQ, He SG et al (2017) Different functional susceptibilities of mouse retinal ganglion cell subtypes to optic nerve crush injury. Exp Eye Res 162:97–103. https://doi.org/10.1016/j.exer.2017.06.014

    Article  CAS  PubMed  Google Scholar 

  35. Kong AW, Della Santina L, Ou Y (2020) Probing ON and OFF retinal pathways in glaucoma using electroretinography. Transl Vis Sci Technol 9:14. https://doi.org/10.1167/tvst.9.11.14

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sun W, Li N, He S (2002) Large-scale morphological survey of mouse retinal ganglion cells. J Comp Neurol 451:115–126. https://doi.org/10.1002/cne.10323

    Article  PubMed  Google Scholar 

  37. Jacoby J, Schwartz GW (2017) Three small-receptive-field ganglion cells in the mouse retina are distinctly tuned to size, speed, and object motion. J Neurosci 37:610–625. https://doi.org/10.1523/jneurosci.2804-16.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Weng S, Sun W, He S (2005) Identification of ON-OFF direction-selective ganglion cells in the mouse retina. J Physiol 562:915–923. https://doi.org/10.1113/jphysiol.2004.076695

    Article  CAS  PubMed  Google Scholar 

  39. Kay JN, De la Huerta I, Kim IJ et al (2011) Retinal ganglion cells with distinct directional preferences differ in molecular identity, structure, and central projections. J Neurosci 31:7753–7762. https://doi.org/10.1523/jneurosci.0907-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Huberman AD, Wei W, Elstrott J et al (2009) Genetic identification of an ON-OFF direction-selective retinal ganglion cell subtype reveals a layer-specific subcortical map of posterior motion. Neuron 62:327–334. https://doi.org/10.1016/j.neuron.2009.04.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mead B, Tomarev S (2016) Evaluating retinal ganglion cell loss and dysfunction. Exp Eye Res 151:96–106. https://doi.org/10.1016/j.exer.2016.08.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Barnstable CJ, Dräger UC (1984) Thy-1 antigen: a ganglion cell specific marker in rodent retina. Neuroscience 11:847–855. https://doi.org/10.1016/0306-4522(84)90195-7

    Article  CAS  PubMed  Google Scholar 

  43. Kwong JM, Caprioli J, Piri N (2010) RNA binding protein with multiple splicing: a new marker for retinal ganglion cells. Invest Ophthalmol Vis Sci 51:1052–1058. https://doi.org/10.1167/iovs.09-4098

    Article  PubMed  PubMed Central  Google Scholar 

  44. Xiang M, Zhou L, Macke JP et al (1995) The Brn-3 family of POU-domain factors: primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons. J Neurosci 15:4762–4785. https://doi.org/10.1523/jneurosci.15-07-04762.1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Iaboni DSM, Farrell SR, Chauhan BC (2020) Morphological multivariate cluster analysis of murine retinal ganglion cells selectively expressing yellow fluorescent protein. Exp Eye Res 196:108044. https://doi.org/10.1016/j.exer.2020.108044

    Article  CAS  PubMed  Google Scholar 

  46. Kim IJ, Zhang Y, Meister M, Sanes JR (2010) Laminar restriction of retinal ganglion cell dendrites and axons: subtype-specific developmental patterns revealed with transgenic markers. J Neurosci 30:1452–1462. https://doi.org/10.1523/JNEUROSCI.4779-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Li Y, Schlamp CL, Nickells RW (1999) Experimental induction of retinal ganglion cell death in adult mice. Invest Ophthalmol Vis Sci 40:1004–1008

    CAS  PubMed  Google Scholar 

  48. Langer KB, Ohlemacher SK, Phillips MJ et al (2018) Retinal ganglion cell diversity and subtype specification from human pluripotent stem cells. Stem Cell Reports 10:1282–1293. https://doi.org/10.1016/j.stemcr.2018.02.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fernandes KA, Harder JM, Williams PA et al (2015) Using genetic mouse models to gain insight into glaucoma: past results and future possibilities. Exp Eye Res 141:42–56. https://doi.org/10.1016/j.exer.2015.06.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Do MTH (2019) Melanopsin and the intrinsically photosensitive retinal ganglion cells: biophysics to behavior. Neuron 104:205–226. https://doi.org/10.1016/j.neuron.2019.07.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Niwa M, Aoki H, Hirata A et al (2016) Retinal cell degeneration in animal models. Int J Mol Sci 17:110. https://doi.org/10.3390/ijms17010110

    Article  CAS  PubMed Central  Google Scholar 

  52. Blanch RJ, Ahmed Z, Berry M, Scott RA, Logan A (2012) Animal models of retinal injury. Invest Ophthalmol Vis Sci 53:2913–2920. https://doi.org/10.1167/iovs.11-8564

    Article  PubMed  Google Scholar 

  53. McKinnon SJ, Schlamp CL, Nickells RW (2009) Mouse models of retinal ganglion cell death and glaucoma. Exp Eye Res 88:816–824. https://doi.org/10.1016/j.exer.2008.12.002

    Article  CAS  PubMed  Google Scholar 

  54. Thomas CN, Thompson AM, Ahmed Z, Blanch RJ (2019) Retinal ganglion cells die by necroptotic mechanisms in a site-specific manner in a rat blunt ocular injury model. Cells 8:1517. https://doi.org/10.3390/cells8121517

    Article  CAS  PubMed Central  Google Scholar 

  55. Bricker-Anthony C, Hines-Beard J, Rex TS (2014) Molecular changes and vision loss in a mouse model of closed-globe blast trauma. Invest Ophthalmol Vis Sci 55:4853–4862. https://doi.org/10.1167/iovs.14-14353

    Article  PubMed  PubMed Central  Google Scholar 

  56. Hines-Beard J, Marchetta J, Gordon S et al (2012) A mouse model of ocular blast injury that induces closed globe anterior and posterior pole damage. Exp Eye Res 99:63–70. https://doi.org/10.1016/j.exer.2012.03.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Thomas CN, Thompson AM, McCance E et al (2018) Caspase-2 mediates site-specific retinal ganglion cell death after blunt ocular injury. Invest Ophthalmol Vis Sci 59:4453–4462. https://doi.org/10.1167/iovs.18-24045

    Article  CAS  PubMed  Google Scholar 

  58. Berkelaar M, Clarke DB, Wang YC, Bray GM, Aguayo AJ (1994) Axotomy results in delayed death and apoptosis of retinal ganglion cells in adult rats. J Neurosci 14:4368–4374. https://doi.org/10.1523/jneurosci.14-07-04368.1994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Osborne NN, Ugarte M, Chao M et al (1999) Neuroprotection in relation to retinal ischemia and relevance to glaucoma. Surv Ophthalmol 43(Suppl 1):S102–S128. https://doi.org/10.1016/s0039-6257(99)00044-2

    Article  PubMed  Google Scholar 

  60. Wareham LK, Calkins DJ (2020) The neurovascular unit in glaucomatous neurodegeneration. Front Cell Dev Biol 8:452. https://doi.org/10.3389/fcell.2020.00452

    Article  PubMed  PubMed Central  Google Scholar 

  61. Krishnan A, Kocab AJ, Zacks DN, Marshak-Rothstein A, Gregory-Ksander M (2019) A small peptide antagonist of the fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma. J Neuroinflammation 16:184. https://doi.org/10.1186/s12974-019-1576-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pease ME, McKinnon SJ, Quigley HA, Kerrigan-Baumrind LA, Zack DJ (2000) Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. Invest Ophthalmol Vis Sci 41:764–774

    CAS  PubMed  Google Scholar 

  63. Sappington RM, Carlson BJ, Crish SD, Calkins DJ (2010) The microbead occlusion model: a paradigm for induced ocular hypertension in rats and mice. Invest Ophthalmol Vis Sci 51:207–216. https://doi.org/10.1167/iovs.09-3947

    Article  PubMed  PubMed Central  Google Scholar 

  64. Tao X, Sabharwal J, Seilheimer RL, Wu SM, Frankfort BJ (2019) Mild intraocular pressure elevation in mice reveals distinct retinal ganglion cell functional thresholds and pressure-dependent properties. J Neurosci 39:1881–1891. https://doi.org/10.1523/jneurosci.2085-18.2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. John SW, Smith RS, Savinova OV et al (1998) Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice. Invest Ophthalmol Vis Sci 39:951–962

    CAS  PubMed  Google Scholar 

  66. Schlamp CL, Li Y, Dietz JA, Janssen KT, Nickells RW (2006) Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric. BMC Neurosci 7:66. https://doi.org/10.1186/1471-2202-7-66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ferreira IL, Duarte CB, Carvalho AP (1996) Ca2+ influx through glutamate receptor-associated channels in retina cells correlates with neuronal cell death. Eur J Pharmacol 302:153–162. https://doi.org/10.1016/0014-2999(96)00044-1

    Article  CAS  PubMed  Google Scholar 

  68. Sánchez-López E, Egea MA, Davis BM et al (2018) Memantine-loaded PEGylated biodegradable nanoparticles for the treatment of glaucoma. Small 14.https://doi.org/10.1002/smll.201701808

  69. Ota T, Hara H, Miyawaki N (2002) Brain-derived neurotrophic factor inhibits changes in soma-size of retinal ganglion cells following optic nerve axotomy in rats. J Ocul Pharmacol Ther 18:241–249. https://doi.org/10.1089/108076802760116160

    Article  CAS  PubMed  Google Scholar 

  70. Hedberg-Buenz A, Christopher MA, Lewis CJ et al (2016) Quantitative measurement of retinal ganglion cell populations via histology-based random forest classification. Exp Eye Res 146:370–385. https://doi.org/10.1016/j.exer.2015.09.011

    Article  CAS  PubMed  Google Scholar 

  71. Chen H, Zhao Y, Liu M et al (2015) Progressive degeneration of retinal and superior collicular functions in mice with sustained ocular hypertension. Invest Ophthalmol Vis Sci 56:1971–1984. https://doi.org/10.1167/iovs.14-15691

    Article  PubMed  PubMed Central  Google Scholar 

  72. Jakobs TC, Libby RT, Ben Y, John SW, Masland RH (2005) Retinal ganglion cell degeneration is topological but not cell type specific in DBA/2J mice. J Cell Biol 171:313–325. https://doi.org/10.1083/jcb.200506099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Feng L, Zhao Y, Yoshida M et al (2013) Sustained ocular hypertension induces dendritic degeneration of mouse retinal ganglion cells that depends on cell type and location. Invest Ophthalmol Vis Sci 54:1106–1117. https://doi.org/10.1167/iovs.12-10791

    Article  PubMed  PubMed Central  Google Scholar 

  74. Davis BM, Guo L, Ravindran N et al (2020) Dynamic changes in cell size and corresponding cell fate after optic nerve injury. Sci Rep 10:21683. https://doi.org/10.1038/s41598-020-77760-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Della Santina L, Inman DM, Lupien CB, Horner PJ, Wong RO (2013) Differential progression of structural and functional alterations in distinct retinal ganglion cell types in a mouse model of glaucoma. J Neurosci 33:17444–17457. https://doi.org/10.1523/jneurosci.5461-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. El-Danaf RN, Huberman AD (2015) Characteristic patterns of dendritic remodeling in early-stage glaucoma: evidence from genetically identified retinal ganglion cell types. J Neurosci 35:2329–2343. https://doi.org/10.1523/jneurosci.1419-14.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Famiglietti EV Jr, Kolb H (1976) Structural basis for ON-and OFF-center responses in retinal ganglion cells. Science 194:193–195. https://doi.org/10.1126/science.959847

    Article  PubMed  Google Scholar 

  78. Cleland BG, Levick WR, Wässle H (1975) Physiological identification of a morphological class of cat retinal ganglion cells. J Physiol 248:151–171. https://doi.org/10.1113/jphysiol.1975.sp010967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ou Y, Jo RE, Ullian EM, Wong RO, Della Santina L (2016) Selective vulnerability of specific retinal ganglion cell types and synapses after transient ocular hypertension. J Neurosci 36:9240–9252. https://doi.org/10.1523/jneurosci.0940-16.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sabharwal J, Seilheimer RL, Tao X et al (2017) Elevated IOP alters the space-time profiles in the center and surround of both ON and OFF RGCs in mouse. Proc Natl Acad Sci U S A 114:8859–8864. https://doi.org/10.1073/pnas.1706994114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wen X, Cahill AL, Barta C, Thoreson WB, Nawy S (2018) Elevated pressure increases Ca(2+) influx through AMPA receptors in select populations of retinal ganglion cells. Front Cell Neurosci 12:162. https://doi.org/10.3389/fncel.2018.00162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wax MB, Tezel G, Yang J et al (2008) Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T-cell-derived fas-ligand. J Neurosci 28:12085–12096. https://doi.org/10.1523/jneurosci.3200-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sappington RM, Sidorova T, Long DJ, Calkins DJ (2009) TRPV1: contribution to retinal ganglion cell apoptosis and increased intracellular Ca2+ with exposure to hydrostatic pressure. Invest Ophthalmol Vis Sci 50:717–728. https://doi.org/10.1167/iovs.08-2321

    Article  PubMed  Google Scholar 

  84. Myhr KL, Lukasiewicz PD, Wong RO (2001) Mechanisms underlying developmental changes in the firing patterns of ON and OFF retinal ganglion cells during refinement of their central projections. J Neurosci 21:8664–8671. https://doi.org/10.1523/jneurosci.21-21-08664.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Muench NA, Patel S, Maes ME et al (2021) The influence of mitochondrial dynamics and function on retinal ganglion cell susceptibility in optic nerve disease. Cells 10:1593. https://doi.org/10.3390/cells10071593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Sladek AL, Nawy S (2020) Ocular hypertension drives remodeling of AMPA receptors in select populations of retinal ganglion cells. Front Synaptic Neurosci 12:30. https://doi.org/10.3389/fnsyn.2020.00030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Duan X, Qiao M, Bei F et al (2015) Subtype-specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mTOR signaling. Neuron 85:1244–1256. https://doi.org/10.1016/j.neuron.2015.02.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Peichl L, Ott H, Boycott BB (1987) Alpha ganglion cells in mammalian retinae. Proc R Soc Lond B Biol Sci 231:169–197. https://doi.org/10.1098/rspb.1987.0040

    Article  CAS  PubMed  Google Scholar 

  89. Peichl L (1991) Alpha ganglion cells in mammalian retinae: common properties, species differences, and some comments on other ganglion cells. Vis Neurosci 7:155–169. https://doi.org/10.1017/s0952523800011020

    Article  CAS  PubMed  Google Scholar 

  90. Krieger B, Qiao M, Rousso DL, Sanes JR, Meister M (2017) Four alpha ganglion cell types in mouse retina: Function, structure, and molecular signatures. PLoS ONE 12:e0180091. https://doi.org/10.1371/journal.pone.0180091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pang JJ, Gao F, Wu SM (2003) Light-evoked excitatory and inhibitory synaptic inputs to ON and OFF alpha ganglion cells in the mouse retina. J Neurosci 23:6063–6073. https://doi.org/10.1523/jneurosci.23-14-06063.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. van Wyk M, Wässle H, Taylor WR (2009) Receptive field properties of ON- and OFF-ganglion cells in the mouse retina. Vis Neurosci 26:297–308. https://doi.org/10.1017/s0952523809990137

    Article  PubMed  PubMed Central  Google Scholar 

  93. Struebing FL, Lee RK, Williams RW, Geisert EE (2016) Genetic networks in mouse retinal ganglion cells. Front Genet 7:169. https://doi.org/10.3389/fgene.2016.00169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Estevez ME, Fogerson PM, Ilardi MC et al (2012) Form and function of the M4 cell, an intrinsically photosensitive retinal ganglion cell type contributing to geniculocortical vision. J Neurosci 32:13608–13620. https://doi.org/10.1523/jneurosci.1422-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bailes HJ, Lucas RJ (2010) Melanopsin and inner retinal photoreception. Cell Mol Life Sci 67:99–111. https://doi.org/10.1007/s00018-009-0155-7

    Article  CAS  PubMed  Google Scholar 

  96. Aranda ML, Schmidt TM (2021) Diversity of intrinsically photosensitive retinal ganglion cells: circuits and functions. Cell Mol Life Sci 78:889–907. https://doi.org/10.1007/s00018-020-03641-5

    Article  CAS  PubMed  Google Scholar 

  97. Schmidt TM, Chen SK, Hattar S (2011) Intrinsically photosensitive retinal ganglion cells: many subtypes, diverse functions. Trends Neurosci 34:572–580. https://doi.org/10.1016/j.tins.2011.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Provencio I, Rollag MD, Castrucci AM (2002) Photoreceptive net in the mammalian retina. This mesh of cells may explain how some blind mice can still tell day from night. Nature 415:493. https://doi.org/10.1038/415493a

    Article  CAS  PubMed  Google Scholar 

  99. Pickard GE, Sollars PJ (2012) Intrinsically photosensitive retinal ganglion cells. Rev Physiol Biochem Pharmacol 162:59–90. https://doi.org/10.1007/112_2011_4

    Article  CAS  PubMed  Google Scholar 

  100. Berson DM, Dunn FA, Takao M (2002) Phototransduction by retinal ganglion cells that set the circadian clock. Science 295:1070–1073. https://doi.org/10.1126/science.1067262

    Article  CAS  PubMed  Google Scholar 

  101. Quattrochi LE, Stabio ME, Kim I et al (2019) The M6 cell: a small-field bistratified photosensitive retinal ganglion cell. J Comp Neurol 527:297–311. https://doi.org/10.1002/cne.24556

    Article  CAS  PubMed  Google Scholar 

  102. Sand A, Schmidt TM, Kofuji P (2012) Diverse types of ganglion cell photoreceptors in the mammalian retina. Prog Retin Eye Res 31:287–302. https://doi.org/10.1016/j.preteyeres.2012.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lee SK, Schmidt TM (2018) Morphological identification of melanopsin-expressing retinal ganglion cell subtypes in mice. Methods Mol Biol 1753:275–287. https://doi.org/10.1007/978-1-4939-7720-8_19

    Article  CAS  PubMed  Google Scholar 

  104. Xiao J, Lin X, Qu J, Zhang J (2021) Morphological and functional diversity of intrinsically photosensitive retinal ganglion cells. Synapse 75:e22200. https://doi.org/10.1002/syn.22200

    Article  CAS  Google Scholar 

  105. Sondereker KB, Stabio ME, Renna JM (2020) Crosstalk: the diversity of melanopsin ganglion cell types has begun to challenge the canonical divide between image-forming and non-image-forming vision. J Comp Neurol 528:2044–2067. https://doi.org/10.1002/cne.24873

    Article  CAS  PubMed  Google Scholar 

  106. Li RS, Chen BY, Tay DK et al (2006) Melanopsin-expressing retinal ganglion cells are more injury-resistant in a chronic ocular hypertension model. Invest Ophthalmol Vis Sci 47:2951–2958. https://doi.org/10.1167/iovs.05-1295

    Article  PubMed  Google Scholar 

  107. Valiente-Soriano FJ, Salinas-Navarro M, Jiménez-López M et al (2015) Effects of ocular hypertension in the visual system of pigmented mice. PLoS ONE 10:e0121134. https://doi.org/10.1371/journal.pone.0121134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Valiente-Soriano FJ, Nadal-Nicolás FM, Salinas-Navarro M et al (2015) BDNF rescues RGCs but not intrinsically photosensitive RGCs in ocular hypertensive albino rat retinas. Invest Ophthalmol Vis Sci 56:1924–1936. https://doi.org/10.1167/iovs.15-16454

    Article  CAS  PubMed  Google Scholar 

  109. Boudard DL, Mendoza J, Hicks D (2009) Loss of photic entrainment at low illuminances in rats with acute photoreceptor degeneration. Eur J Neurosci 30:1527–1536. https://doi.org/10.1111/j.1460-9568.2009.06935.x

    Article  PubMed  Google Scholar 

  110. de Sevilla P, Muller L, Sargoy A, Rodriguez AR, Brecha NC (2014) Melanopsin ganglion cells are the most resistant retinal ganglion cell type to axonal injury in the rat retina. PLoS ONE 9:e93274. https://doi.org/10.1371/journal.pone.0093274

    Article  CAS  Google Scholar 

  111. Nadal-Nicolás FM, Madeira MH, Salinas-Navarro M et al (2015) Transient downregulation of melanopsin expression after retrograde tracing or optic nerve injury in adult rats. Invest Ophthalmol Vis Sci 56:4309–4323. https://doi.org/10.1167/iovs.15-16963

    Article  CAS  PubMed  Google Scholar 

  112. Mao CA, Li H, Zhang Z et al (2014) T-box transcription regulator Tbr2 is essential for the formation and maintenance of Opn4/melanopsin-expressing intrinsically photosensitive retinal ganglion cells. J Neurosci 34:13083–13095. https://doi.org/10.1523/jneurosci.1027-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Nissen C, Sander B, Milea D et al (2014) Monochromatic pupillometry in unilateral glaucoma discloses no adaptive changes subserved by the ipRGCs. Front Neurol 5:15. https://doi.org/10.3389/fneur.2014.00015

    Article  PubMed  PubMed Central  Google Scholar 

  114. Zhang Q, Vuong H, Huang X et al (2013) Melanopsin-expressing retinal ganglion cell loss and behavioral analysis in the Thy1-CFP-DBA/2J mouse model of glaucoma. Sci China Life Sci 56:720–730. https://doi.org/10.1007/s11427-013-4493-1

    Article  CAS  PubMed  Google Scholar 

  115. Zhou Y, Davis AS, Spitze A, Lee AG (2014) Maintenance of pupillary response in a glaucoma patient with no light perception due to persistence of melanopsin ganglion cells. Can J Ophthalmol 49:e20–e21. https://doi.org/10.1016/j.jcjo.2013.10.008

    Article  PubMed  Google Scholar 

  116. La Morgia C, Ross-Cisneros FN, Sadun AA et al (2010) Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies. Brain 133:2426–2438. https://doi.org/10.1093/brain/awq155

    Article  PubMed  PubMed Central  Google Scholar 

  117. Perganta G, Barnard AR, Katti C et al (2013) Non-image-forming light driven functions are preserved in a mouse model of autosomal dominant optic atrophy. PLoS ONE 8:e56350. https://doi.org/10.1371/journal.pone.0056350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Rovere G, Nadal-Nicolas FM, Wang J et al (2016) Melanopsin-containing or non-melanopsin-containing retinal ganglion cells response to acute ocular hypertension with or without brain-derived neurotrophic factor neuroprotection. Invest Ophthalmol Vis Sci 57:6652–6661. https://doi.org/10.1167/iovs.16-20146

    Article  CAS  PubMed  Google Scholar 

  119. Vugler AA, Semo M, Joseph A, Jeffery G (2008) Survival and remodeling of melanopsin cells during retinal dystrophy. Vis Neurosci 25:125–138. https://doi.org/10.1017/s0952523808080309

    Article  PubMed  Google Scholar 

  120. Vaarmann A, Kovac S, Holmström KM, Gandhi S, Abramov AY (2013) Dopamine protects neurons against glutamate-induced excitotoxicity. Cell Death Dis 4:e455. https://doi.org/10.1038/cddis.2012.194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ullian EM, Barkis WB, Chen S, Diamond JS, Barres BA (2004) Invulnerability of retinal ganglion cells to NMDA excitotoxicity. Mol Cell Neurosci 26:544–557. https://doi.org/10.1016/j.mcn.2004.05.002

    Article  CAS  PubMed  Google Scholar 

  122. Jakobs TC, Ben Y, Masland RH (2007) Expression of mRNA for glutamate receptor subunits distinguishes the major classes of retinal neurons, but is less specific for individual cell types. Mol Vis 13:933–948

    CAS  PubMed  PubMed Central  Google Scholar 

  123. González-Menéndez I, Reinhard K, Tolivia J, Wissinger B, Münch TA (2015) Influence of Opa1 mutation on survival and function of retinal ganglion cells. Invest Ophthalmol Vis Sci 56:4835–4845. https://doi.org/10.1167/iovs.15-16743

    Article  CAS  PubMed  Google Scholar 

  124. Georg B, Ghelli A, Giordano C et al (2017) Melanopsin-expressing retinal ganglion cells are resistant to cell injury, but not always. Mitochondrion 36:77–84. https://doi.org/10.1016/j.mito.2017.04.003

    Article  CAS  PubMed  Google Scholar 

  125. Belforte NA, Moreno MC, de Zavalía N et al (2010) Melatonin: a novel neuroprotectant for the treatment of glaucoma. J Pineal Res 48:353–364. https://doi.org/10.1111/j.1600-079X.2010.00762.x

    Article  CAS  PubMed  Google Scholar 

  126. Reiter RJ, Tan D-X (2019) Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells. Melaton Res 2:44–66. https://doi.org/10.32794/mr11250011

    Article  Google Scholar 

  127. González Fleitas MF, Devouassoux J, Aranda ML et al (2021) Melatonin prevents non-image-forming visual system alterations induced by experimental glaucoma in rats. Mol Neurobiol 58:3653–3664. https://doi.org/10.1007/s12035-021-02374-1

    Article  CAS  PubMed  Google Scholar 

  128. Chang CC, Huang TY, Chen HY et al (2018) Protective effect of melatonin against oxidative stress-induced apoptosis and enhanced autophagy in human retinal pigment epithelium cells. Oxid Med Cell Longev 2018:9015765. https://doi.org/10.1155/2018/9015765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Li SY, Yau SY, Chen BY et al (2008) Enhanced survival of melanopsin-expressing retinal ganglion cells after injury is associated with the PI3 K/Akt pathway. Cell Mol Neurobiol 28:1095–1107. https://doi.org/10.1007/s10571-008-9286-x

    Article  CAS  PubMed  Google Scholar 

  130. Hannibal J, Fahrenkrug J (2004) Target areas innervated by PACAP-immunoreactive retinal ganglion cells. Cell Tissue Res 316:99–113. https://doi.org/10.1007/s00441-004-0858-x

    Article  CAS  PubMed  Google Scholar 

  131. Wang T, Li Y, Guo M et al (2021) Exosome-mediated delivery of the neuroprotective peptide PACAP38 promotes retinal ganglion cell survival and axon regeneration in rats with traumatic optic neuropathy. Front Cell Dev Biol 9:659783. https://doi.org/10.3389/fcell.2021.659783

    Article  PubMed  PubMed Central  Google Scholar 

  132. Zhang Y, Kim IJ, Sanes JR, Meister M (2012) The most numerous ganglion cell type of the mouse retina is a selective feature detector. Proc Natl Acad Sci U S A 109:E2391–E2398. https://doi.org/10.1073/pnas.1211547109

    Article  PubMed  PubMed Central  Google Scholar 

  133. Liu X, Feng L, Shinde I et al (2020) Correlation between retinal ganglion cell loss and nerve crush force-impulse established with instrumented tweezers in mice. Neurol Res 42:379–386. https://doi.org/10.1080/01616412.2020.1733322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Luo X, Heidinger V, Picaud S et al (2001) Selective excitotoxic degeneration of adult pig retinal ganglion cells in vitro. Invest Ophthalmol Vis Sci 42:1096–1106

    CAS  PubMed  Google Scholar 

  135. Bell K, Rosignol I, Sierra-Filardi E et al (2020) Age related retinal ganglion cell susceptibility in context of autophagy deficiency. Cell Death Discov 6:21. https://doi.org/10.1038/s41420-020-0257-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Yan W, Peng YR, van Zyl T et al (2020) Cell atlas of the human fovea and peripheral retina. Sci Rep 10:9802. https://doi.org/10.1038/s41598-020-66092-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Teotia P, Niu M, Ahmad I (2020) Mapping developmental trajectories and subtype diversity of normal and glaucomatous human retinal ganglion cells by single-cell transcriptome analysis. Stem Cells 38:1279–1291. https://doi.org/10.1002/stem.3238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Mure LS, Vinberg F, Hanneken A, Panda S (2019) Functional diversity of human intrinsically photosensitive retinal ganglion cells. Science 366:1251–1255. https://doi.org/10.1126/science.aaz0898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ohlemacher SK, Langer KB, Fligor CM et al (2019) Advances in the differentiation of retinal ganglion cells from human pluripotent stem cells. Adv Exp Med Biol 1186:121–140. https://doi.org/10.1007/978-3-030-28471-8_5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Esquiva G, Lax P, Pérez-Santonja JJ, García-Fernández JM, Cuenca N (2017) Loss of melanopsin-expressing ganglion cell subtypes and dendritic degeneration in the aging human retina. Front Aging Neurosci 9:79. https://doi.org/10.3389/fnagi.2017.00079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Hughes S, Watson TS, Foster RG, Peirson SN, Hankins MW (2013) Nonuniform distribution and spectral tuning of photosensitive retinal ganglion cells of the mouse retina. Curr Biol 23:1696–1701. https://doi.org/10.1016/j.cub.2013.07.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Bleckert A, Schwartz GW, Turner MH, Rieke F, Wong RO (2014) Visual space is represented by nonmatching topographies of distinct mouse retinal ganglion cell types. Curr Biol 24:310–315. https://doi.org/10.1016/j.cub.2013.12.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Ito A, Tsuda S, Kunikata H et al (2019) Assessing retinal ganglion cell death and neuroprotective agents using real time imaging. Brain Res 1714:65–72. https://doi.org/10.1016/j.brainres.2019.02.008

    Article  CAS  PubMed  Google Scholar 

  144. Nadal-Nicolás FM, Jiménez-López M, Sobrado-Calvo P et al (2009) Brn3a as a marker of retinal ganglion cells: qualitative and quantitative time course studies in naive and optic nerve-injured retinas. Invest Ophthalmol Vis Sci 50:3860–3868. https://doi.org/10.1167/iovs.08-3267

    Article  PubMed  Google Scholar 

  145. García-Ayuso D, Di Pierdomenico J, Esquiva G et al (2015) Inherited photoreceptor degeneration causes the death of melanopsin-positive retinal ganglion cells and increases their coexpression of Brn3a. Invest Ophthalmol Vis Sci 56:4592–4604. https://doi.org/10.1167/iovs.15-16808

    Article  CAS  PubMed  Google Scholar 

  146. Weber AJ, Kaufman PL, Hubbard WC (1998) Morphology of single ganglion cells in the glaucomatous primate retina. Invest Ophthalmol Vis Sci 39:2304–2320

    CAS  PubMed  Google Scholar 

  147. Nadal-Nicolas FM, Sobrado-Calvo P, Jimenez-Lopez M, Vidal-Sanz M, Agudo-Barriuso M (2015) Long-term effect of optic nerve axotomy on the retinal ganglion cell layer. Invest Ophthalmol Vis Sci 56:6095–6112. https://doi.org/10.1167/iovs.15-17195

    Article  PubMed  Google Scholar 

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Funding

This work was supported by the Provincial Natural Science Foundation of Hubei Province (Grant number 2020CFB240) and the Fundamental Research Funds for the Central Universities (Grant number 2042020kf0065).

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NZ and NY initiated this study and drafted the manuscript. NZ, XH, YX, and NY summarized all the relevant literature and wrote and edited the manuscript. All authors have read and approved the final manuscript for publication.

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Correspondence to Ning Yang.

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Zhang, N., He, X., Xing, Y. et al. Differential susceptibility of retinal ganglion cell subtypes against neurodegenerative diseases. Graefes Arch Clin Exp Ophthalmol 260, 1807–1821 (2022). https://doi.org/10.1007/s00417-022-05556-2

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