Pathoconnectome Analysis of Müller Cells in Early Retinal Remodeling

Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1185)


Glia play important roles in neural function, including but not limited to amino acid recycling, ion homeostasis, glucose metabolism, and waste removal. During retinal degeneration and subsequent retinal remodeling, Müller cells (MCs) are the first cells to show metabolic and morphological alterations in response to stress. Metabolic alterations in MCs chaotically progress in retina undergoing photoreceptor degeneration; however, what relationship these alterations have with neuronal stress, synapse maintenance, or glia-glia interactions is currently unknown. The work described here reconstructs a MC from a pathoconnectome of early retinal remodeling retinal pathoconnectome 1 (RPC1) and explores relationships between MC structural and metabolic phenotypes in the context of neighboring neurons and glia. Here we find variations in intensity of osmication inter- and intracellularly, variation in small molecule metabolic content of MCs, as well as morphological alterations of glial endfeet. RPC1 provides a framework to analyze these relationships in early retinal remodeling through ultrastructural reconstructions of both neurons and glia. These reconstructions, informed by quantitative metabolite labeling via computational molecular phenotyping (CMP), allow us to evaluate neural-glial interactions in early retinal degeneration with unprecedented resolution and sensitivity.


Retinal remodeling Müller cells Connectomics Pathoconnectome Ultrastructure Early retinal degeneration 



This work was supported by the National Institutes of Health R01 EY015128, RO1 EY028927, P30 EY014800, T32 EY024234; and an Unrestricted Research Grant from Research to Prevent Blindness, New York, NY to the Department of Ophthalmology & Visual Sciences, University of Utah.


  1. Anderson JR, Jones BW, Watt CB et al (2011) Exploring the retinal connectome. Mol Vis 17:355–379PubMedPubMedCentralGoogle Scholar
  2. Bignami A, Dahl D (1979) The radial glia of Müller in the rat retina and their response to injury. An immunofluorescence study with antibodies to the glial fibriallary acidic (GFA) protein. Exp Eye Res 28:63–69CrossRefGoogle Scholar
  3. Erickson PA, Fisher SK, Anderson DH et al (1983) Retinal detachment in the cat: the outer nuclear and outer plexiform layers. Invest Ophthalmol Vis Sci 24:927–942PubMedGoogle Scholar
  4. Erickson PA, Fisher SK, Guerin CJ et al (1987) Glial fibrillary acidic protein increases in Muller cells after retinal detachment. Exp Eye Res 44:37–48CrossRefGoogle Scholar
  5. Fariss RN, Li ZY, Milam AH (2000) Abnormalities in rod photoreceptors, amacrine cells, and horizontal cells in human retinas with retinitis pigmentosa. Am J Ophthalmol 129:215–223CrossRefGoogle Scholar
  6. Fisher SK, Lewis GP (2003) Muller cell and neuronal remodeling in retinal detachment and reattachment and their potential consequences for visual recovery: a review and reconsideration of recent data. Vis Res 43:887–897CrossRefGoogle Scholar
  7. Jones BW, Kondo M, Terasaki H et al (2012) Retinal remodeling. Jpn J Ophthalmol 56:289–306CrossRefGoogle Scholar
  8. Jones BW, Pfeiffer RL, Ferrell WD et al (2016a) Retinal remodeling in human retinitis pigmentosa. Exp Eye Res 150:149–165CrossRefGoogle Scholar
  9. Jones BW, Pfeiffer RL, Ferrell WD et al (2016b) Retinal remodeling and metabolic alterations in human AMD. Front Cell Neurosci 10:103PubMedPubMedCentralGoogle Scholar
  10. Jones BW, Watt CB, Frederick JM et al (2003) Retinal remodeling triggered by photoreceptor degenerations. J Comp Neurol 464:1–16CrossRefGoogle Scholar
  11. Jones BW, Kondo M, Terasaki H et al (2011) Retinal remodeling in the Tg P347L rabbit, a large-eye model of retinal degeneration. J Comp Neurol 519:2713–2733CrossRefGoogle Scholar
  12. Kondo M, Sakai T, Komeima K et al (2009) Generation of a transgenic rabbit model of retinal degeneration. Invest Ophthalmol Vis Sci 50:1371–1377CrossRefGoogle Scholar
  13. Marc RE, Murry RF, Fisher SK et al (1998) Amino acid signatures in the detached cat retina. Invest Ophthalmol Vis Sci 39:1694–1702PubMedGoogle Scholar
  14. Pfeiffer RL, Marc RE, Kondo M et al (2016) Muller cell metabolic chaos during retinal degeneration. Exp Eye Res 150:62–70CrossRefGoogle Scholar
  15. Reichenbach A, Bringmann A (2010) Muller cells in the healthy retina. In: Muller cells in the healthy and diseased retina. Springer Science+Business Meddia, LLCGoogle Scholar
  16. Reichenbach A, Bringmann A (2013) New functions of Muller cells. Glia 61:651–678CrossRefGoogle Scholar
  17. Reichenbach A, Schneider H, Leibnitz L et al (1989) The structure of rabbit retinal Muller (glial) cells is adapted to the surrounding retinal layers. Anat Embryol (Berl) 180:71–79CrossRefGoogle Scholar
  18. Shen W, Fruttiger M, Zhu L et al (2012) Conditional Mullercell ablation causes independent neuronal and vascular pathologies in a novel transgenic model. J Neurosci 32:15715–15727CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Departments of OphthalmologyMoran Eye Center, University of UtahSalt Lake CityUSA
  2. 2.Departments of OphthalmologyMie University Graduate School of MedicineTsuJapan
  3. 3.Departments of OphthalmologyNagoya University, Graduate School of MedicineNagoyaJapan
  4. 4.Departments of OphthalmologySignature ImmunologicsTorreyUSA

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