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L. Feng, J. H. Jara, S. M. Riordan, B. Liu, G. Feng, S. M. Lin, J. B. Troy, L. H. Pinto, A. P. Tanna, M. R. Hernandez; Retinal Ganglion Cells (RGCs) in nob4 (no b-wave) Mice Are Less Vulnerable Against Ocular Hypertension (OHT). Invest. Ophthalmol. Vis. Sci. 2009;50(13):2774.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the retinal gene expression under elevated intraocular pressure (IOP) in C57BL/6J and nob4 mice over time. Nob4 mice lack functional metabotropic glutamate receptor 6 (mGluR6).
3 months old C57BL/6J wild type (WT, n=48) and nob4 mice (n=48) were laser photocoagulated on limbus of right eye (OD), left eye (OS) used as control. IOP was measured using TonoLab. RNA, optic nerves, retinas and FluoroGold retrograde labeled whole-mounts from fellow and treated retina were harvested for microarray, quantitative RT-PCR (qRT-PCR), and axonal/neuronal counting at different time points (1-2-4-8 weeks). All values are mean ± SD.
IOP baseline (mmHg) in WT was 14.6±1.4 (OD) vs. 14.3±1.0 (OS). After 3 days post-laser, IOP of OD went up to 31.5±3.8 and remained elevated for 8 weeks. Nob4 exhibited comparable total axon numbers in OS and IOP baseline (15.4±0.6 vs. 15.1±0.5), and similar IOP elevation course vs. WT. The axonal loss in WT-OHT is 20.6±3.8% (2w), 26.9±2.1% (4w), and 32.5±2.2% (8w), decreasing in nob4-OHT as 9.0±0.7%, 10.0±0.3%, and 13.8±0.6%, respectively. The reduction of total RGCs number was 19.8±1.5% vs. 7.7±0.8% after 4w (WT vs. nob4). Microarray analysis revealed unique regulated genes in nob4-OHT including EAAC1, EAAT1, EAA3, Gpx3, Mgst1, and Bag3. qRT-PCR showed that ceruloplasmin (Cp) and Gadd45B levels were high at all times (p<0.001) compared to WT-OHT. Expressions of GFAP and Vim, markers of Müller cell/astrocyte activation were upregulated in both nob4-OHT and WT-OHT at all times (p<0.001).
Decreased axonal/neuronal loss in nob4 OHT model suggests that RGCs in nob4 are more resistant to OHT effects than that of WT. Gene ontology identified unique functional gene groups in nob4 OHT model associated with different cellular events, i.e. extracellular glutamate modulation (EAAC1, EAAT1, EAA3), glutathione metabolism (Gpx3, Mgst1), and neuroprotection (Cp, Gadd45B, Bag3), indicating that there is an intrinsic neuroprotective mechanism for RGCs against elevated IOP in nob4.
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