Vigabatrin-induced retinal functional alterations and second-order neuron plasticity in C57BL/6J mice

Kore Chan, Mrinalini Hoon, Bikash R. Pattnaik, James N. Ver Hoeve, Brad Wahlgren, Shawna Gloe, Jeremy Williams, Brenna Wetherbee, Julie A. Kiland, Kara R. Vogel, Erwin Jansen, Gajja Salomons, Dana Walters, Jean Baptiste Roullet, K. Michael Gibson, Gillian J. McLellan*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

PURPOSE. Vigabatrin (VGB) is an effective antiepileptic that increases concentrations of inhibitory γ -aminobutyric acid (GABA) by inhibiting GABA transaminase. Reports of VGB-associated visual field loss limit its clinical usefulness, and retinal toxicity studies in laboratory animals have yielded conflicting results. METHODS. We examined the functional and morphologic effects of VGB in C57BL/6J mice that received either VGB or saline IP from 10 to 18 weeks of age. Retinal structure and function were assessed in vivo by optical coherence tomography (OCT), ERG, and optomotor response. After euthanasia, retinas were processed for immunohistochemistry, and retinal GABA, and VGB quantified by mass spectrometry. RESULTS. No significant differences in visual acuity or total retinal thickness were identified between groups by optomotor response or optical coherence tomography, respectively. After 4 weeks of VGB treatment, ERG b-wave amplitude was enhanced, and amplitudes of oscillatory potentials were reduced. Dramatic rod and cone bipolar and horizontal cell remodeling, with extension of dendrites into the outer nuclear layer, was observed in retinas of VGB-treated mice. VGB treatment resulted in a mean 3.3-fold increase in retinal GABA concentration relative to controls and retinal VGB concentrations that were 20-fold greater than brain. CONCLUSIONS. No evidence of significant retinal thinning or ERG a- or b-wave deficits were apparent, although we describe significant alterations in ERG b-wave and oscillatory potentials and in retinal cell morphology in VGB-treated C57BL/6J mice. The dramatic concentration of VGB in retina relative to the target tissue (brain), with a corresponding increase in retinal GABA, offers insight into the pathophysiology of VGB-associated visual field loss.

Original languageEnglish
Article number17
JournalInvestigative Ophthalmology and Visual Science
Volume61
Issue number2
DOIs
Publication statusPublished - Feb 2020

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