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Retinal glucose metabolism in mice lacking the L-glutamate/aspartate transporter

Published online by Cambridge University Press:  01 July 2004

VIJAY P. SARTHY ,
V. JOSEPH DUDLEY  and
KOHICHI TANAKA
VIJAY P. SARTHY
Affiliation:
Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago
V. JOSEPH DUDLEY
Affiliation:
Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago
KOHICHI TANAKA
Affiliation:
Laboratory of Molecular Neuroscience, School of Biomedical Science and Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
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Abstract

The conventional view that glucose is the substrate for neuronal energy metabolism has been recently challenged by the “lactate shuttle” hypothesis in which glutamate cycling in glial cells drives all neuronal glucose metabolism. According to this view, glutamate released by activated retinal neurons is transported into Müller (glial) cells where it triggers glycolysis. The lactate released by Müller cells serves as the energy substrate for neuronal metabolism. Because the L-Glutamate/aspartate transporter (GLAST) is the predominant, Na+-dependent, glutamate transporter expressed by Müller cells, we have used GLAST-knockout (GLAST−/−) mice to examine the relationship between lactate release and GLAST activity in the retina. We found that glucose uptake and lactate production by the GLAST−/− mouse retina was similar to that observed in the wild type mouse retina. Furthermore, addition of 1 mM glutamate and NH4Cl to the incubation medium did not further stimulate glucose uptake in either case. When lactate release was measured in the presence of the lactate uptake inhibitor, α-cyano-4-hydroxycinnamate, there was no significant change in the amount of lactate released by retinas from GLAST−/− mice compared to the wild type. Finally, lactate release was similar under both dark and light conditions. These results show that lactate production and release is not altered in retinas of GLAST−/− mice, which suggests that metabolic coupling between photoreceptors and Müller cells is not mediated by the glial glutamate transporter, GLAST.

Keywords

Müller cellGlutamateα-Cyano-4-hydroxycinnamateGLASTLactate
Type
Research Article
Information
Visual Neuroscience , Volume 21 , Issue 4 , July 2004 , pp. 637 - 643
Copyright
2004 Cambridge University Press

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References

REFERENCES

Ames, A., III & Li, Y-Y. (1992). Energy requirements of glutamatergic pathways in rabbit retina. Journal of Neuroscience 12, 4234–4242.Google Scholar
Basinger, S.F., Gordon, W.C., & Lam, D.M.K. (1979). Differential labeling of retinal neurons by 3H-2-deoxyglucose. Nature 280, 682–684.Google Scholar
Bradford, M.M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry 72, 248–254.Google Scholar
Bergersen, L., Johannsson, E., Veruki, M.L., Nagelhus, E.H., Halestrap, A., Sejersted, O.M., & Ottersen, O.P. (1999). Cellular and subcellular expression of monocarboxylate transporters in the pigment epithelium and retina of the rat. Neuroscience 90, 319–331.Google Scholar
Chih, C.-P., Lipton, P., & Roberts, E.L., Jr. (2001). Do active cerebral neurons really use lactate rather than glucose? Trends in Neuroscience 24, 573–578.Google Scholar
Clarke, D.D. & Sokoloff, L. (1994) Circulation and energy metabolism of the brain. In Basic Neurochemistry, ed. Siegel, G.J., Agranoff, B.W., Albers, R.W. & Molinoff, P.B., New York: Raven Press, pp. 645–680.
Coles, J.A., Vega, C., & Marcaggi, P. (2000). Metabolic trafficking between cells in nervous tissue. Progress in Brain Research 125, 241–254.Google Scholar
Dimmer, K.S., Friedrich, B., Lang, F., Deitmer, J.W., & Broer, S. (2000). The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochemical Journal 350, 219–227.Google Scholar
Gerhart, D.Z., Leino, R.L., & Drewes, L.R. (1999). Distribution of monocarboxylate transporters MCT1 and MCT2 in rat retina. Neuroscience 92, 367–375.Google Scholar
Gjedde, A., Marrett, S., & Manouchehr, V. (2002). Oxidative and non-oxidative metabolism of excited neurons and astrocytes. Journal of Cerebral Blood Flow & Metabolism 22, 1–14.Google Scholar
Halestrap, A.P. & Price, N.T. (1999). The proton-linked monocarboxylate transporter (MCT) family: Structure, function and regulation. Biochemical Journal 343, 281–299.Google Scholar
Harada, T., Harada, C., Watanabe, M., Inoue, Y., Sakagawa, T., Nakayama, N., Sasaki, S., Okuyama, S., Watase, K., Wada, K.K., & Tanaka, K. (1998). Functions of two glutamate transporters GLAST and GLT-1 in the retina. Proceedings of the National Academy of Science of the U.S.A. 95, 4663–4666.Google Scholar
Hsu, S.-C. & Molday, R.S. (1991). Glycolytic enzymes and GLUT1 glucose transporter in the outer segments of rod and cone photoreceptor cells. Journal of Biological Chemistry 266, 21745–21752.Google Scholar
Magistretti, P.J., Pellerin, L., Rothman, D.L., & Shulman, R.G. (1999). Energy on demand. Science 283, 496–497.Google Scholar
McKenna, M.C., Hopkins, I.B., & Carey, A. (2001). α-cyano-4-hydroxycinnamate decreases both glucose and lactate metabolism in neurons and astrocytes: Implications for lactate as an energy substrate for neurons. Journal of Neuroscience Research 66, 747–754.Google Scholar
Meeks, J.P. & Mennerick, S. (2003). Feeding hungry neurons: Astrocytes deliver food for thought. Neuron 37, 187–189.Google Scholar
Pellerin, L. & Magistretti, P.J. (1994). Glutamate uptake into astrocytes stimulates aerobic glycolysis: A mechanism coupling neuronal activity to glucose utilization. Proceedings of the National Academy of Sciences of the U.S.A. 91, 10625–10629.Google Scholar
Poitry, S., Poitry-Yamate, C., Ueberfeld, J., MacLeish, P.R., & Tsacopoulos, M. (2000). Mechanisms of glutamate metabolic signaling in retinal glial (Müller) cells. Journal of Neuroscience 20, 1809–1821.Google Scholar
Poitry-Yamate, C., Poitry, S., & Tsacopoulos, M. (1995). Lactate released by Müller glial cells is metabolized by photoreceptors from mammalian retina. Journal of Neuroscience 15, 5179–5191.Google Scholar
Poitry-Yamate, C.L. & Tsacopoulos, M. (1991). Glial (Müller) cells take up and phosphorylate 3H-2-doxyglucose in a mammalian retina. Neuroscience Letters 122, 241–244.Google Scholar
Poitry-Yamate, C.L. & Tsacopoulos, M. (1992). Glucose metabolism in freshly isolated Müller glial cells from a mammalian retina. Journal of Comparative Neurology 320, 257–266.Google Scholar
Ransom, C.B., Ransom, B.R., & Sonthheimer, H. (2000). Activity-dependent extracellular accumulation in rat optic nerve: The role of glial and axonal Na+ pumps. Journal of Physiology 522, 427–442.Google Scholar
Rauen, T., Rothstein, J.D., & Wassle, H. (1996). Differential expression of three glutamate transporter subtypes in the rat retina. Cell and Tissue Research 286, 325–336.Google Scholar
Schurr, A., Payne, R.S., Miller, J.J., & Rigor, B.M. (1997). Brain lactate is an obligatory aerobic energy substrate for functional recovery after hypoxia: Further in vitro validation. Journal of Neurochemistry 69, 423–426.Google Scholar
Sperling, H.G., Harcombe, E.S., & Johnson, C. (1982). Stimulus-controlled labeling of cones in the macaque retina with 3H-2-deoxyglucose. In The Structure of the Eye, ed. Hollyfield, J., pp. 55–60. Paris: Elsevier.
Stone, C. & Pinto, L.H. (1993). Response properties of ganglion cells in the isolated mouse retina. Visual Neuroscience 10, 31–39.Google Scholar
Tsacopoulos, M. & Magistretti, P.J. (1996). Metabolic coupling between glia and neurons. Journal of Neuroscience 16, 877–885.Google Scholar
Tsacopoulos, M., Poitry-Yamate, C.L., McLeish, P.R., & Poitry, S. (1998). Trafficking of molecules and metabolic signals in the retina. Progress in Retina and Eye Research 17, 429–442.Google Scholar
Vega, C., Martiel, J.-C., Drouhault, D., Burckhart, M.-F., & Coles, J.A. (2003). Uptake of locally applied deoxyglucose, glucose and lactate by axons and Schwann cells of rat vagus nerve. Journal of Physiology 546, 551–564.Google Scholar
Volk, C., Kempski, B., & Kempski, O.S. (1997). Inhibition of lactate export by quercetin acidifies rat glial cells in vitro. Neuroscience Letters 223, 121–124.Google Scholar
Voutsinos-Porsche, B., Bonvento, G., Tanaka, K., Steiner, P., Welker, E., Chatton, J.-Y., Magistretti, P.J., & Pellerin, L. (2003). Glial glutamate transporters mediate a functional metabolic cross talk between neurons and astrocytes in the mouse developing cortex. Neuron 39, 275–286.Google Scholar
Watase, K., Hashimoto, K., Kano, M., Yamada, K., & Watanabe, K.M. (1998). Motor discordination and increased susceptibility to cerebellar injury in GLAST mutant mice. European Journal of Neuroscience 10, 976–988.Google Scholar
Wender, R., Brown, A.M., Fern, R., Swanson, R.A., Farrell, K., & Ransom, B.R. (2000). Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. Journal of Neuroscience 20, 6804–6810.Google Scholar
Winkler, B. (1981). Glycolytic and oxidative metabolism in relation to retinal function. Journal of General Physiology 77, 667–692.Google Scholar
Winkler, B.S. (1989). Editorial comments. Retinal aerobic glycolysis revisited. Investigative Ophthalmology and Visual Science 30, 1023.Google Scholar
Winkler, B.S. (1995). A quantitative assessment of glucose metabolism in the isolated rat retina. In Les Seminaires Ophthalmologiques d'IPSEN: Vision et Adaptation, ed. Christen, Y., Doly, C-Y. & Droy-LeFaix, M.-T., pp. 78–96. Amsterdam: Elsevier.
Winkler, B.S., Aronol, M.J., Brassell, M.S., & Puro, D.G. (2000). Energy metabolism in human Müller cells. Investigative Ophthalmology and Visual Science 41, 3183–3190.Google Scholar
Winkler, B.S., Pourcho, R.G., Starnes, C., Slocum, J., & Slocum, N. (2003). Metabolic mapping in mammalian retina: A biochemical and 3H-2-Deoxyglucose autoradiographic study. Experimental Eye Research 77, 327–337.Google Scholar
Winkler, B.S., Sauer, M.W., & Starnes, C.A. (2004). The effects of l-glutamate/d-aspartate and monensin on lactic acid production in retina and cultured Müller cells. Journal of Neurochemistry 89, 514–525.Google Scholar
Witkovsky, P. & Yang, C.-Y. (1982). Uptake and localization of 3H-deoxyglucose by retinal photoreceptors. Journal of Comparative Neurology 204, 105–116.Google Scholar
Zeevalk, G.D. & Nicklas, W.J. (2000). Lactate prevents the alterations in tissue amino acids, decline in ATP, and cell damage due to aglycemia in retina. Journal of Neurochemistry 75, 1027–1034.Google Scholar