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Kore Chan, Brad Wahlgren, Shawna Gloe, James N Ver Hoeve, Mrinalini Hoon, Bikash R Pattnaik, Jeremy Williams, Julie A Kiland, Erwin Jansen, Gajja Salomons, Dana Walters, Jean-Baptiste Roullet, K Michael Gibson, Gillian J McLellan; Vigabatrin-induced retinal bipolar cell plasticity in C57BL/6J mice. Invest. Ophthalmol. Vis. Sci. 2019;60(9):968.
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© ARVO (1962-2015); The Authors (2016-present)
Vigabatrin (VGB) is an effective anti-epileptic that increases concentrations of inhibitory γ-aminobutyric acid (GABA) through irreversible inhibition of GABA transaminase but reports of peripheral visual field defects (pVFD) limit its clinical utility. Retinal toxicity studies in laboratory animals have yielded conflicting results. We examined functional and morphological effects of VGB administration in C57BL/6J mice.
10 week old C57BL/6J mice, housed under a 12 hour, 120 lux light:dark cycle, received either VGB (140mg/kg) or vehicle (saline) by I.P. injection for 60d. Retinal structure and function were assessed in vivo by optical coherence tomography (OCT), electroretinography (ERG) under scotopic and photopic conditions (flash intensities 0.001-20 cd*s/m^2) and quantitative optomotor response (qOMR) at baseline and every two weeks thereafter. After euthanasia, retinas were processed for immunohistochemistry and retinal GABA and VGB quantified by tandem mass spectrometry.
Scotopic and photopic flash ERG demonstrated no significant deficits in a-, b- or c-wave amplitudes or latencies, Naka-Rushton function coefficients or Fourier transform harmonics between vehicle and VGB-treated groups. After 2-6 weeks of VGB treatment, b-wave amplitude intensity-response was enhanced in VGB-treated mice. No degradation of visual acuity was identified by qOMR. OCT and immunohistochemistry revealed no significant differences in total retinal or retinal layer thicknesses between groups. Numbers of photoreceptor nuclei, rod bipolar cells and GABA- and glycinergic amacrine cells were not significantly different between groups, but dramatic rod bipolar cell remodeling with extension of dendrites into the photoreceptor layer was observed in VGB-treated retinas (Figure 1, arrowheads). In VGB-treated mice relative to controls, retinal GABA was increased 3.3-fold compared to vehicle, while retinal VGB (active S-(+) isomer) was concentrated 5-fold compared to brain and liver.
In contrast to previous reports in pigmented mice, we did not identify evidence of significant retinal thinning or ERG deficits in VGB-treated C57BL/6J mice. Further studies are underway to determine whether observed bipolar cell abnormalities are primary or secondary to other retinal cell pathology and to elucidate the complex pathogenesis of visual dysfunction in VGB-treated patients.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
Rod bipolar cell remodeling in VGB-treated retinas
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