Abstract
Purpose :
To ensure adequate oxygenation of the retina, one of the most metabolically demanding tissues in the body, photoreceptors are mainly supplied by the choroid and inner retinal neurons by the retinal vasculature. Vascular damage in retinal degenerative diseases, e.g. diabetic retinopathy, or attenuated retinal blood vessel development in retinopathy of prematurity (ROP) result in retinal hypoxia. We tested whether hypoxia underlies compromised phototransduction and light signal transmission, and whether changes are reversible, by measuring photoreceptor (PR) and ON-bipolar cell (ON-BC) light responses in mouse models of these conditions.
Methods :
Diabetic (db/db) and non-diabetic (db/+) mice were used as a diabetes model. For oxygen-induced retinopathy (OIR, a model of ROP), we exposed C57BL/6J pups to high (75%) O2 from postnatal day (P)7 to P12, before returning them to room air. We recorded scotopic in vivo electroretinograms (ERGs) or ex vivo ERGs in isolated retinas. To modulate O2 concentrations we provided hypoxic gas (8% O2) through a nose cone in vivo or perfused with hypoxic superfusate (containing 2.5% O2) ex vivo.
Results :
ON-BCs lose function within 8 minutes of ex vivo hypoxia, whereas PRs retain >50% response amplitudes after 30 min (n=2-3). In vivo PR and ON-BC amplitudes in diabetic mice progressively decrease at 4.5 and 6, but not at 3 months. Diabetes reduces the b/a-wave ratio at 6 months (2.20±0.23 in db/db compared to 2.65±0.27 in db/+, p= P<0.001, n=9-10), indicating that ON-BCs or light signal transmission are more susceptible to diabetes than phototransduction. During ex vivo ERG (with 95% O2) PR and ON-BC responses were not different between 6 month old db/db and db/+ mice (n=11). Ex vivo PR and ON-BC function were reduced in OIR mice on P12 (n=7-10, P<0.001) and on P24 (n=8-10, P<0.001).
Conclusions :
Although retinal neurons critically depend on sufficient O2 supply, PRs maintain better function during hypoxia compared to ON-BCs, possibly by adapting to low O2 conditions they are exposed to daily during the normal light-dark cycle. Deficits in retinal function in diabetic mice in vivo are reversed ex vivo with high O2. Irreversible PR damage in OIR likely occurs during the hyperoxic phase, before hypoxic damage. Investigating these discrepancies will allow us to better understand importance and therapeutic potential of adequate O2 supply in different retinal diseases.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.