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.