Abstract
Retinitis pigmentosa (RP) is a progressive retinal dystrophy that causes visual impairment and eventual blindness. Retinal prostheses are the best currently available vision-restoring treatment for RP, but only restore crude vision. One possible contributing factor to the poor quality of vision achieved with prosthetic devices is the pathological retinal ganglion cell (RGC) hyperactivity that occurs in photoreceptor dystrophic disorders. Gap junction blockade with meclofenamic acid (MFA) was recently shown to diminish RGC hyperactivity and improve the signal-to-noise ratio (SNR) of RGC responses to light flashes and electrical stimulation in the rd10 mouse model of RP. We sought to extend these results to spatiotemporally patterned optogenetic stimulation in the faster-degenerating rd1 model and compare the effectiveness of a number of drugs known to disrupt rd1 hyperactivity. We crossed rd1 mice with a transgenic mouse line expressing the light-sensitive cation channel channelrhodopsin2 (ChR2) in RGCs, allowing them to be stimulated directly using high-intensity blue light. We used 60-channel ITO multielectrode arrays to record ChR2-mediated RGC responses from wholemount, ex-vivo retinas to full-field and patterned stimuli before and after application of MFA, 18-β-glycyrrhetinic acid (18BGA, another gap junction blocker) or flupirtine (Flu, a Kv7 potassium channel opener). All three drugs decreased spontaneous RGC firing, but 18BGA and Flu also decreased the sensitivity of RGCs to optogenetic stimulation. Nevertheless, all three drugs improved the SNR of ChR2-mediated responses. MFA also made it easier to discern motion direction of a moving bar from RGC population responses. Our results support the hypothesis that reduction of pathological RGC spontaneous activity characteristic in retinal degenerative disorders may improve the quality of visual responses in retinal prostheses and they provide insights into how best to achieve this for optogenetic prostheses.
Highlights
Retinitis pigmentosa (RP) is a retinal dystrophy characterized by progressive photoreceptor death, starting with the rods, causing night-blindness and a loss of peripheral vision, followed eventually by total blindness as the cones start to degenerate as well (Heckenlively et al, 1988; Berson, 1993; Hartong et al, 2006)
Each drug significantly reduced the strength of local field potential (LFP) oscillations (Friedman test: 18BGA n = 7, p = 2.5 × 10−5; Flu n = 7, p = 0.0001; meclofenamic acid (MFA) n = 7, p = 6 × 10−6) and spontaneous retinal ganglion cell (RGC) firing (Friedman test: 18BGA n = 7, p = 1.1 × 10−5; Flu n = 7, p = 6 × 10−6; MFA n = 7, p = 1.5 × 10−5)
Flu has a stronger effect at low concentrations, consistent with a previous study showing that 10 μM Flu blocks spontaneous activity (Choi et al, 2014), but for all three drugs spontaneous firing is almost completely abolished at 80 μM
Summary
Retinitis pigmentosa (RP) is a retinal dystrophy characterized by progressive photoreceptor death, starting with the rods, causing night-blindness and a loss of peripheral vision, followed eventually by total blindness as the cones start to degenerate as well (Heckenlively et al, 1988; Berson, 1993; Hartong et al, 2006). Current retinal prostheses use implanted electrodes in combination with photovoltaics (Mathieson et al, 2012; Stingl et al, 2013) or an external light sensor (Dorn et al, 2013) to deliver patterned electrical stimulation to the retina and evoke a visual percept (Margalit et al, 2002), but far such devices have only managed to restore crude vision (Dorn et al, 2013; Stingl et al, 2013) Possible reasons for this include limited resolution due to the low number of electrodes (presently 60–1500, Dorn et al, 2013; Stingl et al, 2013), lack of control over the spatial spread of charge, lack of cell-type specificity and the ability to provide excitatory but not inhibitory stimulation (Barrett et al, 2014). The past decade has seen considerable progress in the development of optogenetic retinal prostheses, in which surviving inner retinal neurons are made light sensitive to restore vision (for review, see Busskamp and Roska, 2011; Busskamp et al, 2012; Cepko, 2012; Sahel and Roska, 2013; Barrett et al, 2014)
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