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W. Huang, J. h. Zou, G. R. Howell, S. W. M. John, D. Krizaj; Plasticity of Calcium Signaling Pathways in the DBA/2J Mouse Model. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2778.
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© ARVO (1962-2015); The Authors (2016-present)
Neurodegeneration is driven and sustained by changes in intracellular calcium signaling in neuronal and glial cells. Here, we investigated whether development and maintenance of glaucomatous reorganization of the inner retina is associated with changes in expression and/or localization of key plasma membrane and intracellular Ca store channels and transporters. Postnatal ages preceding axonal loss (1-5 months) and degenerating retinas were analyzed.
IOP measurements, PPD staining and quantitative RT-PCR were performed in retinas from wild type C57BL6, DBA/2J and DBA/2J mice with the wild type Gpnmb gene. Axonal counts were performed using the PPD staining method and glaucomatous injury rated on a 1-5 scale; the injury in each retina was correlated with changes in RGC markers Brn3a and VGLUT2, activated glial marker GFAP and microglial markers Iba1 and CD11. Age-matched samples from 1 week, and 1, 3, 5, 7. 12 and 15 month old animals were studied (n=at least 12 animals per condition). Western blots were performed for a subset of calcium transporters. qPCR was performed using the GAPDH standard.
IOP was elevated in aged DBA/2J mice from 11±2 mm Hg in 1 month-old DBA mice to 41±10 mm Hg in 12 month-old mice; comparable IOP in wild type 12 month-old mice was 10±8 mm Hg. The degree of axonal loss in DBAs was correlated with the loss of Brn3a and VGLU2 mRNA. Minor changes in expression of CACNAD and CACNAF genes were observed in 1-9 month old DBA mice with a significant increase in Cav 1.3 (70 ± 20%; P<0.05) and PMCA1 (94+2%, P<0.05) at 15 months. A 161±31% to 670±81% increase was observed in the expression of RyR1, but not RyR2, 3 isoforms, at all ages. Increased RyR1 levels were correlated with increases in GFAP, CD11 and Iba1, with a concomitant decrease in glutamine synthetase mRNA. Immunostaining suggested increased ryanodine receptor expression in retinal glia.
Glaucomatous reorganization of the inner retina is not associated with major changes in expression of plasma membrane voltage-operated calcium channels and NCX & PMCA transporters. However, an upregulation and re-distribution of internal store Ca release channels in retinal glia suggests a major contribution to local signaling in the inner retina both before and during axonal loss.
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