Transcriptome analysis in mice treated with vigabatrin identifies dysregulation of genes associated with retinal signaling circuitry.
Gene expression
RNA sequencing (RNAseq)
Retina
Transcriptome
Vigabatrin
Visual field constriction
Journal
Epilepsy research
ISSN: 1872-6844
Titre abrégé: Epilepsy Res
Pays: Netherlands
ID NLM: 8703089
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
06
04
2020
revised:
02
06
2020
accepted:
09
06
2020
pubmed:
18
7
2020
medline:
7
10
2021
entrez:
18
7
2020
Statut:
ppublish
Résumé
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 fiber layer (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 (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.
Identifiants
pubmed: 32679486
pii: S0920-1211(20)30220-5
doi: 10.1016/j.eplepsyres.2020.106395
pmc: PMC7494645
mid: NIHMS1613642
pii:
doi:
Substances chimiques
Anticonvulsants
0
Vigabatrin
GR120KRT6K
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
106395Subventions
Organisme : NEI NIH HHS
ID : R01 EY027476
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
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