Transcriptome analysis in mice treated with vigabatrin identifies dysregulation of genes associated with retinal signaling circuitry

Abstract

Vigabatrin (VGB; γ-vinyl-GABA) is an antiepileptic drug that elevates CNS GABA via irreversible inactivation of the GABA catabolic enzyme GABA-transaminase. VGB's clinical utility, however, can be curtailed by peripheral visual field constriction (pVFC) and thinning of the retinal nerve layer fiber (RNFL). Earlier studies from our laboratory revealed disruptions of autophagy by VGB. Here, we tested the hypothesis that VGB administration to animals would reveal alterations of gene expression in VGB-treated retina that associated with autophagy. VGB (140 mg/kg/d; subcutaneous minipump) was continuously administered to mice (n=6 each VGB/ vehicle) for 12 days, after which animals were euthanized. Retina was isolated for transcriptome (RNAseq) analysis and further validation using qRT-PCR and immunohistochemistry (IHC). For 112 differentially expressed retinal genes (RNAseq), two databases s (Gene Ontology; Kyoto Encyclopedia of Genes and Genomes) were used to identify genes associated with visual function. Twenty four genes were subjected to qRT-PCR validation, and five (Gb5, Bdnf, Cplx9, Crh, Sox9) revealed significant dysregulation. IHC of fixed retinas verified significant down-regulation of Gb5 in photoreceptor cells. All of these genes have been previously shown to play a role in retinal function/circuitry signaling. Minimal impact of VGB on retinal autophagic gene expression was observed. This is the first transcriptome analysis of retinal gene expression associated with VGB intake, highlighting potential novel molecular targets potentially related to VGB's well known ocular toxicity.

Testing for pharmacogenomic predictors of ppRNFL thinning in individuals exposed to vigabatrin

“…We then compared the gene-based testing results with previously published gene-expression analysis. Walters et al identified 26 ocular function genes, that showed evidence of differential expression in mice exposed to VGB, compared to the controls ( Walters et al, 2020 ). We examined these 26 genes in our analyses to see if there was an enrichment of gene-based signal.…”

“…We cross referenced results of our gene-based testing with 26 genes with ocular function that were previously shown to be differentially expressed in mice exposed to VGB, compared to the controls ( Walters et al, 2020 ).…”