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Editors Selection IGR 9-3

Basic research: Glutamate

John Danias

Comment by John Danias on:

13560 Assessment of glutamate loss from the ganglion cell layer of young DBA/2J mice with glaucoma, Low HC; Gionfriddo JR; Madl JE, American Journal of Veterinary Research, 2006; 67: 302-309

See also comment(s) by Elizabeth WoldeMussie & Larry Wheeler


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The DBA/2 mouse is an appealing animal model for the study of glaucoma as its retinal and optic nerve pathology have close similarities to the human disease. Glutamate excitotoxicity has previously been suggested as the cause of glaucomatous neurodegeneration. Low et al. (379) investigated whether glutamate content is decreased in retinal ganglion cells (RGCs) of DBA/2 mice compared with similarly aged non-glaucomatous mice. The authors used immunoglod labeling to address this question. They found that even in young DBA/2 mice, they could histologically detect 'damaged' RGCs. In areas with large numbers of 'damaged' RGCs, the percentage of cells strongly immunolabelled for glutamate was reduced compared with that in areas with few 'damaged' RGCs and that in non-glaucomatous mice. The authors conclude that glutamate loss from RGCs may contribute to excitotoxic RGC death prior to IOP elevation.

This study has a number of serious methodological problems. RGCs are defined as 'damaged' on purely histologic criteria without any other evidence of retinal dysfunction. In addition, the method used to fix the tissue is not rapid enough for fixing a small, rapidly diffusing molecule like glutamate. Even though immunogold labeling can be used to obtain reasonably quantitative data, it has to be performed with extreme care and multiple controls, which are clearly missing here. The authors also fail to explain why they do not detect increased glutamate immunoreactivity in Muller cells as they find in glaucomatous dogs and would be expected if glutamate leaks out of RGCs.

Despite these limitations, this is the only study to support the findings of Schuettauf et al.1 who report retinal changes in DBA/2 mice before IOP elevation, in contrast to the work of many other groups.2-7 Since the animals used in the Low study were obtained from the same supplier (JAX) but housed at the author's institution, modulation of the timing and intensity of glaucomatous neurodegeneration by environmental factors may explain this apparent discrepancy.

References

  1. Schuettauf F, Rejdak R, Walski M, Frontczak-Baniewicz M, Voelker M, Blatsios G, Shinoda K, Zagorski Z, Zrenner E, Grieb P. Retinal neurodegeneration in the DBA/2J mouse-a model for ocular hypertension. Acta Neuropathol (Berl) 2004; 107: 352-358.
  2. Danias J, Lee KC, Zamora MF, Chen B, Shen F, Filippopoulos T, Su Y, Goldblum D, Podos SM, Mittag T. Quantitative analysis of retinal ganglion cell (RGC) loss in aging DBA/2NNia glaucomatous mice: comparison with RGC loss in aging C57/BL6 mice. Invest Ophthalmol Vis Sci 2003; 44: 5151-5162.
  3. Bayer AU, Neuhardt T, May AC, Martus P, Maag KP, Brodie S, Lütjen-Drecoll E, Podos SM, Mittag T. Retinal morphology and ERG response in the DBA/2NNia mouse model of angle-closure glaucoma. Invest Ophthalmol Vis Sci, 2001; 42: 1258-1265.
  4. Jakobs TC, Libby RT, Ben Y, John SW, Masland RH, Retinal ganglion cell degeneration is topological but not cell type specific in DBA/2J mice. J Cell Biol 2005; 171: 313-325.
  5. Libby RT, Anderson MG, Pang IH, Robinson ZH, Savinova OV, Cosma IM, Snow A, Wilson LA, Smith RS, Clark, John SW. Inherited glaucoma in DBA/2J mice: pertinent disease features for studying the neurodegeneration. Vis Neurosci 2005; 22: 637-648.
  6. Moon JI, Kim IB, Gwon JS, Park MH, Kang TH, Lim EJ, Choi KR, Chun MH. Changes in retinal neuronal populations in the DBA/2J mouse. Cell Tissue Res 2005; 320: 51-59.
  7. Sheldon WG, Warbritton AR, Bucci TJ, Turturro A. Glaucoma in food-restricted and ad libitum-fed DBA/2NNia mice. Lab Anim Sci 1995; 45: 508-518.


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