Investigating the role of caspase-1 in a mouse model of juvenile X-linked retinoschisis

Abstract

Purpose : Previous studies have reported caspase-1 is upregulated in murine models of juvenile X-linked retinoschisis (JXLR). We performed electroretinogram (ERG) and standardized optical coherence tomography (OCT) in Casp1^-/-/Rs1-KO double knock out mice to test the hypothesis that caspase-1 may play a role in disease evolution.

Methods : Casp1^-/-/Rs1-KO double knock out (DKO) mice were generated by breeding Rs1-KO mice with Casp1^-/- mice. OCT imaging was analyzed at 2 and 4 months of age. Outer nuclear layer (ONL) thickness and adapted standardized cyst severity score were measured and averaged from 4 locations 500 um from the optic nerve. Adapted standardized cyst severity score was 1: absent cysts, 2: <30 um, 3: 30-49 um, 4: 50-69 um, 5: 70-99 um, 6: >99 um. Electroretinograms (ERG) were recorded in dark adapted and light adapted conditions at 2 and 4 months. Results obtained from Rs1-KO (n=5 mice, 10 eyes) and DKO (n=3 mice, 6 eyes) mice were compared with age matched WT control mice (n=3 mice, 6 eyes).

Results : Intraretinal cysts were never seen on OCT in WT mice, while schisis was apparent in most Rs1-KO and DKO mice. There was no difference in cyst score or ONL thickness at 2 months of age between Rs1-KO and DKO. All ERG amplitudes were markedly reduced in Rs1-KO and DKO compared to WT controls at 2 months old. There was a trend for lower ERG amplitudes in all testing conditions in the DKO mice compared to Rs1-KO mice. Electronegative dark adapted 3.0 bright flash ERG was seen in 3/6 eyes of DKO mice (averaged b/a 1.106), and 0/10 eyes in Rs1-KO mice (averaged b/a 1.223) at 2 months of age (Figure 1).

Conclusions : Elimination of caspase-1 in Rs1-KO mice does not ameliorate the early ERG or OCT abnormalities. Although caspase-1 has been reported to be upregulated in Rs1 mice, our preliminary data suggest that removing caspase-1 is not beneficial early in life. Longer follow up may reveal changes later in the disease course.

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

 

Examples of dark adapted 3.0 electroretinogram showing low b-wave in Rs1-KO mice (a), electronegative b-wave in Rs1/Casp1 DKO mice (b), and normal waveform with well preserved a- and b-wave in a wild type control mice at 2 months of age.