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J. C. Morrison, Y. Guo, J. A. Dyck, W. O. Cepurna, T. Doser, E. C. Johnson; Glaucoma Model Gene Expression Responses in the Retinal Ganglion Cell Layer : BDNF, TrkB and p75NTR. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2760. doi: https://doi.org/.
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Disrupted supply of BDNF and its receptor, TrkB, is hypothesized to trigger retinal ganglion cell (RGC) death in glaucoma, and the death signal is thought to be mediated by the alternative receptor, p75NTR. However, evidence confirming neurotrophin deprivation in RGCs and p75NTR-mediated apoptosis is limited. In this study, we examined expression of BDNF and its receptors in the RGC layer (RGCL) in a rat glaucoma model to refine our previous studies using whole retinas.
Chronic IOP elevation was produced unilaterally in Brown Norway rats by episcleral vein injection of hypertonic saline (n=37). Total RNA was extracted from laser capture microdissected RGCL, linearly amplified and reverse transcribed for quantitative real time PCR (qPCR). Optic nerve injury was graded on a 1(no injury) to 5 (active degeneration involving the total nerve area) scale. BDNF, TrkB, and p75NTR mRNA levels were determined in fellows (n=13) and three nerve injury groups (minimal injury: grade<1.5, n=18; focal injury: 1.5<grade< 4.5, n=12; global injury: grade >4.5, n=7). Levels of Nefh and Brn3b (RGC), Gfap (astrocytes), Aif (microglia), and Stx1a (amacrines) were determined to characterize RGCL composition.
A comparison between the RGCL and whole retina results (all in percent of control values) are summarized in the table. Both analyses yielded similar expression changes, except for Brn3b, BDNF and p75NTR. Brn3b declined linearly in RGCL (r2=0.29, p<0.01) while no significant change was detected in whole retina. In RGCL, BDNF was significantly increased, in contrast to stable values in whole retinas. Also, while p75NTR was linearly upregulated in the whole retina (r2=0.395, p<0.01), no increase was seen in the RGCL analysis.
IOP elevation results in an endogenous BDNF upregulation and TrkB downregulation in the RGCL. Simultaneously, RGCL p75NTR is downregulated, which may indicate an attempt to enhance cell survival. These RCGL findings refine the whole retina analysis, allowing us to examine changes of the neurotrophin signaling system that are more relevant to mechanisms of RGC damage in glaucoma.
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