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Sylvia B Smith, Jing Wang, Alan Saul, Xuezhi Cui, Penny Roon; Absence of Sigma 1 Receptor (σ1R) accelerates photoreceptor cell (PRC) loss in Pde6brd10/J (rd10) mice.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2732.
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© 2017 Association for Research in Vision and Ophthalmology.
σ1R, a 25.3 KDa transmembrane protein located in ER, mitochondrial and nuclear membranes, is a putative molecular chaperone present in multiple cell types (retinal ganglion cells, Müller glial cells (MGCs), PRCs). Our recent findings (Wang et al, FRBM, 2015) suggest that σ1R may also modulate retinal oxidative stress because MGCs harvested from mice lacking σ1R (σ1R-/-) have significantly decreased expression of Nrf2, a major antioxidant protein that controls expression of >500 oxidative/cytoprotective genes. Since MGCs maintain/support retinal neurons, we hypothesized that PRC death, characteristic of rd10 mice, would be accelerated in the absence of σ1R. Rd10 mice lose rod PRCs beginning at P18; by P35 many cones are lost and cone function is minimal.
Rd10 and σ1R-/- mice were bred to generate double knockout mice. C57BL6J (WT) (n=18), rd10 (n=20), rd10/σ1R-/- (n=22) mice were subjected to ERG (age P28), OCT (P24), FA (P24) to assess visual function/structure in situ. Eyes were harvested, processed for embedding, imaged microscopically and subjected to morphometric analysis (P29, P35). Data were analyzed using GraphPad prism (ANOVA, paired mean tests).
Rd10 mice had reduced retinal function and fewer PRCs compared to WT mice; the phenotype worsened in double knockout mice. Scotopic ERG b-wave amplitude was significantly decreased in rd10/σ1R-/- mice compared to rd10 mice (90±12 v 148±14 µV, p=0.001); photopic responses were markedly reduced compared to rd10 mice (31±6 v 56±7 µV, p<0.05). OCT revealed reduced retinal thickness in rd10/σ1R-/- mice compared to rd10 mice (120±5.5 v. 132.1±8.1 µm, p<0.5). Compared to WT, vascular filling detected by FA was delayed in rd10 mice and vessel diameter attenuated; this was exaggerated in rd10/σ1R-/- mice and included vessel leakiness. Morphometric analysis revealed significantly fewer PRCs in rd10/σ1R-/- versus rd10 mice at P29 (80.5±10.3 v 125.3±20.3 PRCs/225µm retinal length (RL), p<0.001) & at P35 (41.3±13.9 v 106.9±6.9 PRCs/225µm RL, p<0.001).
In the absence of σ1R, rd10 visual function and PRC survival are even more severely compromised compared to WT than rd10 mice with σ1R. The data indicate that retinal susceptibility to pathological processes increases when σ1R is absent suggesting that this protein may play a key role in modulating retinal cellular stress.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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