Investigating the Role of Retinal Dehydrogenase 14 in Cone Pigment Regeneration

Abstract

Purpose : The regeneration of cone visual pigment and the dark adaptation of cones are driven by two parallel pathways: the retinal pigmented epithelium (RPE) visual cycle that produces 11-cis retinal, and the Müller cell-driven retina visual cycle that produces 11-cis retinol, which is accessible exclusively to cones. The enzyme converting 11-cis retinol produced by Müller cells to 11-cis retinal (11-cis RDH) in the retina visual cycle has not been identified yet. RDH14 is expressed in the retinal pigmented epithelium, Müller cells, and photoreceptors, and has been shown to have 11-cis RDH activity. Thus, here we investigated the role of RDH14 in the timely supply of visual chromophore to cones required for their function as daytime photoreceptors.

Methods : Rdh14^flox/flox mice were created commercially and crossed with Hrgp-Cre⁺Gnat1^−/− mice to produce Rdh14^flox/floxHrgp-Cre⁺Gnat1^−/− (Rdh14^Δcone) mice to delete RDH14 selectively in cone cells and facilitate cone recordings. Counterpart Rdh14^flox/flox Hrgp-Cre^- Gnat1^−/− were used as control. The role of RDH14 on cone function in darkness and during dark adaptation was studies by ex vivo transretinal recordings and in vivo electroretinography (ERG).

Results : The transretinal waveform and the amplitude of M-cone dim flash responses and saturating responses were comparable between control and Rdh14^Δcone dark-adapted retinas. Following a bright >90% pigment bleach, the kinetics of cone dark adaptation was also comparable between control and Rdh14^Δcone retinas. ERG recordings in vivo confirmed the normal function of RDH14-deficient cones in dark-adapted conditions. However, the ERG recordings also revealed that cones in Rdh14^Δcone mice were desensitized to a greater extent by the end of 30 min exposure to 300 cd/m² bright green background light, and their subsequent dark adaptation was suppressed compared to controls.

Conclusions : Our preliminary data suggest that RDH14 does not affect the dark-adapted function of mouse M-cone photoreceptors. However, reduced sensitivity and suppressed cone dark adaptation in vivo following prolonged exposure to bright background light suggests that RDH14 might be required for the efficient long-term supply of chromophore to cones.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.