Knocking out Stat3 in rod photoreceptor cells unexpectedly protects against light-induced retinal degeneration

Abstract

Purpose : Signal transducer and activator of transcription 3 (Stat3) is involved in many signaling pathways. Ueki, et al. (2008) found that Stat3 activation in photoreceptors is associated with protection from light damage. Therefore, we hypothesized that knocking out Stat3 in rod photoreceptor cells would exacerbate loss of retina function in a light-induced retinal degeneration (LIRD) mouse model.

Methods : Stat3^flox mice were bred onto a C57BL/6J Rpe65^L450/L450 background (this strain with this allele is more sensitive to LIRD than mice with the M450 allele, which is found in most common research strains). These mice were bred to Rho-iCRE75 mice, which have a rod-specific CRE. Male and female mice were genotyped for Rho-iCRE75, Stat3-floxed allele, and Rpe65-L450 allele, then evenly distributed into bright or dim light exposure groups for a total of 13 to 17 mice per group. Mice were dark-adapted overnight. The following morning mice were given 1% atropine eye drops and then exposed to dim (50 lux) or bright (40,000 lux) light for 4 hours beginning at 10:30 am. Scotopic electroretinograms (ERGs) were performed one week later to assess retina function. ERG data were analyzed using two-way ANOVA with Tukey’s Multiple Comparisons test for mean a- and b-wave amplitudes and one-way ANOVA for c-waves.

Results : Diminution of a-wave amplitudes was seen in both control and Rho-iCRE75 Stat3-floxed mice following LIRD. Less diminution was seen in the Rho-iCRE75 Stat3-floxed mice and there was a statistically significant difference between the mean a-wave amplitudes between the two genotypes in the light damage cohorts (P<0.0001). There was no statistical difference between dim groups. Similar outcomes were observed with c-wave amplitudes between the LIRD groups (P=0.0006). Mean b-wave amplitudes were significantly different in both bright and dim groups, with greater mean amplitudes in the Rho-iCRE75 Stat3-floxed mice (Dim P=0.0466, Bright P=0.0044)

Conclusions : Unexpectedly, knocking out Stat3 in rod photoreceptors does not exacerbate loss of retina function due to light damage. In fact, there is modest functional protection of a- and c-waves. As this is unexpected, we are further characterizing the effects of knocking out Stat3 in rod photoreceptors and we are creating additional strains to test the effects of knocking out Stat3 in other retina cell types.

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