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Delores A. Stacks, Marci L DeRamus, Carrie E Huisingh, Gerald McGwin, Timothy W Kraft, Steven J Pittler; ERG Analysis of the Murine GARP2 Knockout: Abnormal Retinal Function. Invest. Ophthalmol. Vis. Sci. 2017;58(8):275. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Glutamic acid-rich protein, GARP2, is the most abundantly expressed of three photoreceptor (PR) proteins encoded by the Cngb1 locus which also encodes GARP1, and the β-subunit of the cyclic nucleotide-gated cation channel. In our GARP2 knockout mice (GARP2-KO), we previously reported changes in the appearance of the retinal pigment epithelium (RPE) including displaced melanosomes and regional perturbations in the PR/RPE interdigitation zone, in which the PR outer segments appear longer and parallel to the RPE microvillus processes. Here, we tested for electrophysiological consequences of the observed morphologic changes.
All testing was done on 3-month-old WT (n=8) and GARP2-KO (n=9) mice on a C57Bl/6J background. Functional testing included scotopic ERG with increasing flash intensities, photopic ERG to a saturating flash, scotopic and photopic flicker ERG, and scotopic c-wave. Phototransduction gain, critical flicker fusion threshold (CFF), stimulus required to evoke half maximum response (I50), and c-wave area analyses were performed in IgorPro 6 with Wilcoxon ranked sum statistics performed with SAS software (significance p ≤ 0.05).
Scotopic a- and b- waves were reduced 33% and 50% respectively in the GARP2-KO (a: 256±91 µV, b: 499±183 µV) compared to WT (a:384±112 µV, b: 990±225 µV). Photopic a- and b-waves were also reduced (a: GARP2-KO 128±51 µV, WT 208±68 µV; b: GARP2-KO 168±59 µV, WT 428±128 µV). Assuming linearity between b-wave amplitude and area under the c-wave curve, a significant reduction in c-wave was observed in the GARP2-KO for two scotopic intensities (by 23% and 28% respectively). Scotopic CFF was reduced by 29.4% in GARP2-KO (15.1 ± 1.4 Hz) vs WT (21.4 ± 2.6 Hz). No significant changes were observed in gain, photopic CFF, or the I50.
Our results are consistent with a GARP2 role in modulating PR responses. Although there is likely some damage to the cone-driven circuits (loss of photopic a-, and b-wave maximum amplitudes) the threshold detection of flicker (photopic CFF) is maintained. The rod signaling pathway seems to be more affected, indicated by the significantly reduced scotopic CFF. Reduced c-waves in the GARP2-KO indicate that GARP2 may also affect RPE/PR potassium ion flow, particularly under conditions where the PR response is primarily rod-driven.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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