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Metabolic Changes Associated With Müller Cells In A Transgenic Rabbit Model Of Retinal Degeneration

Retina RLP

This abstract was presented today at the 2014 Association for Research in Vision and Opthalmology (ARVO) meetings in Orlando, Florida by  Rebecca L. Pfeiffer, Bryan W. Jones and Robert E. Marc.

Purpose: Müller cells play a central role in retinal metabolism via the glutamate cycle. During retinal degeneration Müller cells are among the first to demonstrate changes, reflected in alterations of metabolic signatures and morphology. The timing, extent and regulation of these changes is not fully characterized. To address this issue, we evaluated Müller cell metabolic phenotypes at multiple stages of retinal remodeling.

Methods: Samples were collected post-mortem from both WT and P347L rabbits. The retinas were then divided into fragments, fixed in buffered aldehydes, and embedded in epoxy resins. Tissues were sectioned at 200nm followed by classification with computational molecular phenotyping (CMP) using an array of small and macromolecular signatures (aspartate (D), glutamate (E), glycine (G), glutamine (Q), glutathione (J), GABA (yy), taurine (T), CRALBP, Glutamine Synthetase (GS), and GFAP). Levels of amino acid or protein were quantified by selecting a region of interest either within the Müller cell population or surrounding neurons and evaluating the intensity of the signal within that region.

Results: CMP reveals overall decreases in GS levels over the course of degeneration. Of notable importance, we saw that in regions of near complete photoreceptor loss neighboring Müller cells may express independent variation in metabolic signatures of E, Q, and GS. Also observed in these Müller cells, ratios of GS:E and GS:Q are not consistent with the ratios seen in WT retina. These results are inconsistent with the current models of both E to Q metabolism and microenvironment regulation of Müller cell phenotypes.

Conclusions: These observations indicate two conclusions. First, although the degenerate state of the retina is the likely trigger inducing Müller cells to express altered metabolic signatures, the rate at which the metabolic state changes is not purely a product of the surrounding environment, but also a stochastic change within individual Müller cells. Second, although it is commonly accepted that GS is the primary enzyme which converts Q to E as part of the glutamate cycle, in degenerate retina alternative pathways may be utilized following decrease in GS.

Support:  NIH EY02576 (RM), NIH EY015128 (RM), NSF 0941717 (RM), NIH EY014800 Vision Core (RM), RPB CDA (BWJ), Thome AMD Grant (BWJ).

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Abstract Human Retina

Human-color-retina

This image of ganglion cells, Müller cells and starburst amacrine cells in the human retina is from a patient suffering from retinitis pigmentosa (RP).  This disease this patient suffered from slowly causes people affected with this disease to go blind and is a constant reminder to me of why we engage in our research.

For some, this is a pretty, though abstract image created through a set of technologies called computational molecular phenotyping (CMP).   The colors in this image come from antibodies labeling taurine, glutamine and glutamate, all small molecular species that reveal metabolic states in these tissues.

For us, these images reveal variation in cell types as well as abnormalities in other kinds of cells that presage retinal stress and the cellular responses that alter the retina in ways that both cause blindness and make it difficult to rescue vision loss.  We also see the beginnings of changes in the circuitry of the retina that forever will alter the way that diseased retinas process information.

Image courtesy of Bryan William Jones, Ph.D. and originally appeared here.

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Interesting Paper: Gene Expression Changes Within Müller Glial Cells in Retinitis Pigmentosa

Retinal degenerations are accompanied by retinal remodeling events.  These events alter the structure and function of the retina and involve to a large extent, Müller cells which seem to serve as pathways for neuronal migration.  This paper by Karin Roesch, Michael B. Stadler and Constance L. Cepko looks at gene expression changes in the Müller cells, one of the glial cells of the retina as the rd1 mouse retina degenerates.

While the paper is not terribly conclusive in its definition of genes or pathways involved, (partially I suspect because of the limited time points examined and the late point in the examinations), this paper does however point in a direction that is useful to the retinal degeneration community.  Specifically, Müller cells are fundamentally involved in the remodeling process.  Intervening there is an opportunity to arrest or slow down the retinal remodeling process to allow for interventions and understanding which genes are involved is a good first step.

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Proliferative reactive gliosis is compatible with glial metabolic support and neuronal function

This paper by Vazquez-Chona FR, Swan A, Ferrell WD, Jiang L, Baehr W, Chien WM, Fero M, Marc RE and Levine EM addresses a long standing issue in the field of neuroscience: is the reactive phenotype of glial cells in and of itself detrimental to neural survival or function?

Continue reading “Proliferative reactive gliosis is compatible with glial metabolic support and neuronal function”