Glia-Neuron Interactions in the Retina Can Be Studied in Cocultures of Müller Cells and Retinal Ganglion Cells

Skytt, Dorte M.; Toft‐Kehler, Anne Katrine; Brændstrup, C.; Cejvanovic, Sanja; Gurubaran, I.S.; Bergersen, Linda Hildegard; Kolko, Miriam

doi:10.1155/2016/1087647

Cited by 37 publications

(27 citation statements)

References 53 publications

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“…Müller glia provide trophic and metabolic support to RGCs during times of stress, including glaucoma related stresses (44,45). Müller glia activation, identified by increased glutamine synthetase (GS) labelling, has been demonstrated in different animal models of glaucoma.…”

Section: No Detectable Müller Glia Activation Following Ocular Hypertmentioning

confidence: 99%

When is a control not a control? Reactive microglia occur throughout the control contralateral visual pathway in experimental glaucoma

Tribble

Kokkali

Otmani

et al. 2019

Preprint

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Background: Glaucoma remains a leading cause of irreversible blindness worldwide. Multiple animal models show retinal ganglion cell injuries that replicate features of glaucoma. In these experiments the contralateral eye is commonly used as an internal control. As in humans, in rodents and non-human primates there is significant cross-over of retinal ganglion cell axons from the ipsilateral to the contralateral side at the level of the optic chiasm which may confound findings when damage is restricted to one eye. While neuroinflammation may be a critical event that damages retinal ganglion cells and their axons during glaucoma progression the effect of unilateral damage on the contralateral visual pathway has largely been unexplored.Methods: Ocular hypertensive glaucoma was induced unilaterally or bilaterally by intracameral injection of paramagnetic beads in adult Brown Norway rats. Retinal ganglion cell neurodegeneration and dysfunction were assessed. Neuroinflammation was quantified in the retina, optic nerve head, optic nerve, lateral geniculate nucleus, and superior colliculus by high resolution imaging, and in the retina by flow cytometry and protein arrays.Results: Following ocular hypertensive stress the retinal vasculature remodels, peripheral monocytes enter the retina, and microglia become highly reactive. This effect is more marked in animals with bilateral induction of ocular hypertensive glaucoma. In rats where glaucoma was induced unilaterally there was significant microglia activation in the contralateral (control) eye. Microglial activation extended into the optic nerve and terminal visual thalami, where it was similar across hemispheres irrespective of whether ocular hypertension was unilateral or bilateral. Conclusions:Ocular hypertensive glaucoma in the rat recapitulates many of the features of human glaucoma. In this model microglia become reactive throughout the visual pathway during glaucoma pathogenesis. These effects are not isolated to the experimental eye and its pathway and significant neuroinflammation occurs in the contralateral 'control' eye and pathway. These data suggest that caution is warranted when using the contralateral eye as control in unilateral models of glaucomatous damage.

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Section: No Detectable Müller Glia Activation Following Ocular Hypertmentioning

confidence: 99%

When is a control not a control? Reactive microglia occur throughout the control contralateral visual pathway in experimental glaucoma

Tribble

Kokkali

Otmani

et al. 2019

Preprint

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“…In addition to glucose and lactate, the alternative metabolic energy substrates, amino acids, have also been proposed to rescue neurons (Skytt et al. ; Lefevere et al. ).…”

Section: Introductionmentioning

confidence: 99%

Potential metabolic markers in glaucoma and their regulation in response to hypoxia

Vohra

Dalgaard

Vibæk

et al. 2019

Acta Ophthalmologica

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Purpose: To assess novel differences in serum levels of glucose, lactate and amino acids in patients with normal-tension glaucoma (NTG) compared to agematched controls, at baseline and in response to universal hypoxia. Methods: Twelve patients diagnosed with NTG and eleven control subjects underwent normobaric hypoxia for 2 hr. Peripheral venous blood samples were taken at baseline, during hypoxia and in the recovery phase. Serum glucose and lactate levels were measured by a blood gas analyser. Amino acids were analysed by high-performance liquid chromatography. Results: Baseline levels of lactate and total amino acids were significantly lower in patients with NTG compared to healthy controls. No differences were seen in blood glucose levels between the two groups. Lactate levels remained unchanged during hypoxia in the control group, but increased in patients with NTG. In the recovery phase, total amino acid levels were reduced in the control group, whereas no changes were found in patients with NTG. Conclusion: Reduced serum levels of lactate and total amino acids were identified as potential markers for NTG. Moreover, significant differential regulatory patterns of certain amino acids were found in patients with NTG compared to control subjects. Overall, our results suggest a link between systemic energy metabolites and NTG and support a novel understanding of glaucoma as an inner retinal manifestation of a systemic condition.

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“…Among multiple essential functions, Müller cells are key components in buffering molecules in the extracellular compartments of the inner retina 1,2 and aid in neuroprotection by removing excessive glutamate from the synapse between bipolar cells and retinal ganglion cells (RGCs) to prevent excitotoxicity. [3][4][5] To facilitate these functions, Müller cells rely heavily on a steady energy production. Müller cell energy metabolism is therefore essential in sustaining RGC survival, thereby reducing the risk of inner retinal conditions, such as glaucoma and diabetic retinopathy.…”

mentioning

confidence: 99%

Dual Properties of Lactate in Müller Cells: The Effect of GPR81 Activation

Vohra

Aldana

Bergersen

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Vohra R, Aldana BI, Waagepetersen H, Bergersen LH, Kolko M. Dual properties of lactate in Müller cells: the effect of GPR81 activation. Invest Ophthalmol Vis Sci. 2019;60:999-1008. https://doi.org/ 10.1167/iovs.18-25458PURPOSE. Besides being actively metabolized, lactate may also function as a signaling molecule by activation of the G-protein-coupled receptor 81 (GPR81). Thus, we aimed to characterize the metabolic effects of GPR81 activation in Müller cells.METHOD. Primary Müller cells from mice were treated with and without 10 mM L-lactate in the presence or absence of 6 mM glucose. The effects of lactate receptor GPR81 activation were evaluated by the addition of 5 mM 3,5-DHBA (3,5-dihydroxybenzoic acid), a GPR81 agonist. Western blot analyses were used to determine protein expression of GPR81. Cell survival was assessed through 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) viability assays. Lactate release was quantified by commercially available lactate kits. 13 Clabeling studies via mass spectroscopy and Seahorse analyses were performed to evaluate metabolism of lactate and glucose, and mitochondrial function. Finally, Müller cell function was evaluated by measuring glutamate uptake.RESULTS. The lactate receptor, GPR81, was upregulated during glucose deprivation. Treatment with a GPR81 agonist did not affect Müller cell survival. However, GPR81 activation diminished lactate release allowing lactate to be metabolized intracellularly. Furthermore, GPR81 activation increased metabolism of glucose and mitochondrial function. Finally, maximal glutamate uptake decreased in response to GPR81 activation during glucose deprivation.CONCLUSIONS. The present study revealed dual properties of lactate via functioning as an active metabolic energy substrate and a regulatory molecule by activation of the GPR81 receptor in primary Müller cells. Thus, combinational therapy of lactate and GPR81 agonists may be of future interest in maintaining Müller cell survival, ultimately leading to increased resistance toward retinal neurodegeneration.

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Glia-Neuron Interactions in the Retina Can Be Studied in Cocultures of Müller Cells and Retinal Ganglion Cells

Cited by 37 publications

References 53 publications

When is a control not a control? Reactive microglia occur throughout the control contralateral visual pathway in experimental glaucoma

When is a control not a control? Reactive microglia occur throughout the control contralateral visual pathway in experimental glaucoma

Potential metabolic markers in glaucoma and their regulation in response to hypoxia

Dual Properties of Lactate in Müller Cells: The Effect of GPR81 Activation

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