AUTHOR=Gehrke Ella J. , Pandey Araniko , Thompson Jacob , Bhattarai Sajag , Gurung Prajwal , Hsu Ying , Drack Arlene V. 

TITLE=Investigating the role of Caspase-1 in a mouse model of Juvenile X-linked Retinoschisis

JOURNAL=Frontiers in Medicine

VOLUME=11

YEAR=2024

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1347599

DOI=10.3389/fmed.2024.1347599

ISSN=2296-858X

ABSTRACT=<sec id="sec1"><title>Purpose</title><p>Previous studies have reported Caspase-1 (<italic>Casp1</italic>) is upregulated in mouse models of Juvenile X-linked Retinoschisis (XLRS), however no functional role for <italic>Casp1</italic> in disease progression has been identified. We performed electroretinogram (ERG) and standardized optical coherence tomography (OCT) in mice deficient in the Retinoschisin-1 (<italic>Rs1</italic>) and <italic>Casp1</italic> and Caspase-11 <italic>(Casp11)</italic> genes (<italic>Rs1</italic>-KO<italic>;Casp1/11<sup>−/−</sup></italic>) to test the hypothesis that <italic>Casp1</italic> may play a role in disease evolution and or severity of disease. Currently, no studies have ventured to investigate the longer-term effects of <italic>Casp1</italic> on phenotypic severity and disease progression over time in XLRS, and specifically the effect on electroretinogram.</p></sec><sec id="sec2"><title>Methods</title><p><italic>Rs1</italic>-KO;<italic>Casp1/11<sup>−/−</sup></italic> mice were generated by breeding <italic>Rs1</italic>-KO mice with <italic>Casp1/11<sup>−/−</sup></italic> mice. OCT imaging was analyzed at 2-, 4-, and 15–16 months of age. Outer nuclear layer (ONL) thickness and adapted standardized cyst severity score were measured and averaged from 4 locations 500 μm from the optic nerve. Adapted standardized cyst severity score was 1: absent cysts, 2: &lt;30 μm, 3: 30–49 μm, 4: 50–69 μm, 5: 70–99 μm, 6: &gt;99 μm. Electroretinograms (ERG) were recorded in dark-adapted and light-adapted conditions at 2 and 4 months. Results obtained from <italic>Rs1</italic>-KO and <italic>Rs1</italic>-KO;<italic>Casp1/11<sup>−/−</sup></italic> eyes were compared with age matched WT control eyes at 2 months.</p></sec><sec id="sec3"><title>Results</title><p>Intraretinal schisis was not observed on OCT in WT eyes, while schisis was apparent in most <italic>Rs1</italic>-KO and <italic>Rs1</italic>-KO;<italic>Casp1/11<sup>−/−</sup></italic> eyes at 2 and 4 months of age. There was no difference in the cyst severity score from 2 to 4 months of age, or ONL thickness from 2 to 16 months of age between <italic>Rs1</italic>-KO and <italic>Rs1</italic>-KO;<italic>Casp1/11<sup>−/−</sup></italic> eyes. ERG amplitudes were similarly reduced in <italic>Rs1</italic>-KO and <italic>Rs1</italic>-KO;<italic>Casp1/11<sup>−/−</sup></italic> compared to WT controls at 2 months of age, and there was no difference between <italic>Rs1-</italic>KO and <italic>Rs1</italic>-KO;<italic>Casp1/11<sup>−/−</sup></italic> eyes at 2 or 4 months of age, suggesting no impact on the electrical function of photoreceptors over time in the absence of <italic>Casp1</italic>.</p></sec><sec id="sec4"><title>Conclusion</title><p>Although <italic>Casp1</italic> has been reported to be significantly upregulated in <italic>Rs1-</italic>KO mice, our preliminary data suggest that removing <italic>Casp1/11</italic> does not modulate photoreceptor electrical function or alter the trajectory of the retinal architecture over time.</p></sec>