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Simon Kaja, Yuliya Naumchuk, Stephanie Grillo, Priscilla Borden, Peter Koulen; Differential overexpression of Homer 1 isoforms is associated with hallmarks of disease and decline in visual performance in a preclinical model of glaucoma. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6099.
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© ARVO (1962-2015); The Authors (2016-present)
Elevated intraocular pressure (IOP) is a major risk factor for glaucomatous optic neuropathy and currently the only target of pharmacological and surgical therapies. However, despite IOP-lowering drugs, degeneration of retinal ganglion cells (RGCs) and the optic nerve continues, ultimately resulting in blindness. Vesl/Homer proteins are scaffolding proteins that are critical for maintaining synaptic integrity by clustering, organizing and functionally regulating synaptic proteins. We here investigated Vesl/Homer expression in the context of impairment of visual function in a preclinical model for glaucoma.
Expression and distribution of Vesl-1/Homer 1 protein isoforms were quantified using quantitative polymerase chain reaction, quantitative immunoblotting and immunohistochemistry in the retinae of DBA/2J mice, a preclinical genetic glaucoma model reminiscent of chronic human pigmentary glaucoma. 6 week- (6wo) and 9 months-old (9mo) DBA/2J mice were used. Expression levels were correlated with disease markers for glaucoma, intraocular pressure, visual acuity and contrast sensitivity.
Expression of the constitutively expressed long Vesl-1L/Homer 1c isoform was increased 4.2±0.8 fold at the transcriptional level in the 9mo glaucomatous DBA/2J retina. Similarly, retinal Homer 1c protein increased by 60 ± 24% in 9mo mice. Immunohistochemistry revealed a characteristic distribution of Homer 1c in the synaptic layers of the retina, specifically in the ganglion cell layer and the outer and inner plexiform layers. Microfluorimetry showed a 3-fold increase in immunoreactivity in 9mo vs. 6wo DBA/2J retinae. Protein levels of Homer 1c were statistically significantly correlated with markers for disease severity, showing a strong positive association with IOP (P<0.01, R2=0.628) and contrast sensitivity (P<0.05, R2=0.562), and a strong negative association with visual acuity (P<0.05, R2=0.618).
The synaptic clustering protein Vesl-1L/Homer 1c is strongly correlated with disease severity of glaucoma in DBA/2J mice. Vesl-1L/Homer 1c represents a novel, druggable target for the future development of anti-glaucoma therapies aimed at reducing hyperexcitability and aberrant neuronal Ca2+ signaling in the glaucomatous retina.
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