TY - JOUR
T1 - Vigabatrin-induced retinal functional alterations and second-order neuron plasticity in C57BL/6J mice
AU - Chan, Kore
AU - Hoon, Mrinalini
AU - Pattnaik, Bikash R.
AU - Ver Hoeve, James N.
AU - Wahlgren, Brad
AU - Gloe, Shawna
AU - Williams, Jeremy
AU - Wetherbee, Brenna
AU - Kiland, Julie A.
AU - Vogel, Kara R.
AU - Jansen, Erwin
AU - Salomons, Gajja
AU - Walters, Dana
AU - Roullet, Jean Baptiste
AU - Gibson, K. Michael
AU - McLellan, Gillian J.
N1 - Funding Information: Supported by NIH R01 EY027476, NIH P30 EY016665, NIH S10 OD018221, NIH T32 EY027721, a Fight for Sight summer student fellowship, and unrestricted funds to the University of Wisconsin-Madison, Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness. Publisher Copyright: Copyright 2020 The Authors. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/2
Y1 - 2020/2
N2 - 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.
AB - 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.
KW - GABA
KW - Mouse
KW - Vigabatrin
UR - http://www.scopus.com/inward/record.url?scp=85079334690&partnerID=8YFLogxK
U2 - https://doi.org/10.1167/iovs.61.2.17
DO - https://doi.org/10.1167/iovs.61.2.17
M3 - Article
C2 - 32053727
SN - 0146-0404
VL - 61
SP - 17
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 2
M1 - 17
ER -