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Blockade of pathological retinal ganglion cell hyperactivity improves optogenetically evoked light responses in rd1 mice.

Barrett JM, Degenaar P, Sernagor E - Front Cell Neurosci (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medical Sciences, Institute of Neuroscience, Newcastle University Newcastle-upon-Tyne, UK.

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.

No MeSH data available.


Related in: MedlinePlus

(A–C) Raw electrode trace on one channel for an example retina in control conditions (A), with 20 μM MFA (B), and with 80 μM MFA (C). Note the decrease in both oscillations and level of spontaneous firing as the drug concentration increases. (D) Power spectra recorded on the same channel in control conditions, at each drug concentration and after washout. Notice the overall decrease in LFP power as the drug concentration increases and the recovery upon washout.
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Figure 1: (A–C) Raw electrode trace on one channel for an example retina in control conditions (A), with 20 μM MFA (B), and with 80 μM MFA (C). Note the decrease in both oscillations and level of spontaneous firing as the drug concentration increases. (D) Power spectra recorded on the same channel in control conditions, at each drug concentration and after washout. Notice the overall decrease in LFP power as the drug concentration increases and the recovery upon washout.

Mentions: Figure 1 shows raw traces recorded from one channel in control conditions and in the presence of 20 μM and 80 μM MFA, as well as the power spectra from this same channel at each drug concentration. There is a clear decrease in oscillatory activity and spontaneous firing as the drug concentration increases. This pattern held across all retinas for all three drugs tested. Each drug significantly reduced the strength of LFP oscillations (Friedman test: 18BGA n = 7, p = 2.5 × 10−5; Flu n = 7, p = 0.0001; MFA n = 7, p = 6 × 10−6) and spontaneous 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). Figure 2 shows the effect of each drug on oscillation strength and spontaneous firing rate relative to control conditions averaged across all recorded channels for all retinas. 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. There is substantial recovery of oscillations and spontaneous firing after washout of Flu and MFA, consistent with previous reports (Menzler and Zeck, 2011; Trenholm et al., 2012; Choi et al., 2014), but not with 18BGA, the effects of which are known to be irreversible at high concentrations (Rozental et al., 2001).


Blockade of pathological retinal ganglion cell hyperactivity improves optogenetically evoked light responses in rd1 mice.

Barrett JM, Degenaar P, Sernagor E - Front Cell Neurosci (2015)

(A–C) Raw electrode trace on one channel for an example retina in control conditions (A), with 20 μM MFA (B), and with 80 μM MFA (C). Note the decrease in both oscillations and level of spontaneous firing as the drug concentration increases. (D) Power spectra recorded on the same channel in control conditions, at each drug concentration and after washout. Notice the overall decrease in LFP power as the drug concentration increases and the recovery upon washout.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4548307&req=5

Figure 1: (A–C) Raw electrode trace on one channel for an example retina in control conditions (A), with 20 μM MFA (B), and with 80 μM MFA (C). Note the decrease in both oscillations and level of spontaneous firing as the drug concentration increases. (D) Power spectra recorded on the same channel in control conditions, at each drug concentration and after washout. Notice the overall decrease in LFP power as the drug concentration increases and the recovery upon washout.
Mentions: Figure 1 shows raw traces recorded from one channel in control conditions and in the presence of 20 μM and 80 μM MFA, as well as the power spectra from this same channel at each drug concentration. There is a clear decrease in oscillatory activity and spontaneous firing as the drug concentration increases. This pattern held across all retinas for all three drugs tested. Each drug significantly reduced the strength of LFP oscillations (Friedman test: 18BGA n = 7, p = 2.5 × 10−5; Flu n = 7, p = 0.0001; MFA n = 7, p = 6 × 10−6) and spontaneous 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). Figure 2 shows the effect of each drug on oscillation strength and spontaneous firing rate relative to control conditions averaged across all recorded channels for all retinas. 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. There is substantial recovery of oscillations and spontaneous firing after washout of Flu and MFA, consistent with previous reports (Menzler and Zeck, 2011; Trenholm et al., 2012; Choi et al., 2014), but not with 18BGA, the effects of which are known to be irreversible at high concentrations (Rozental et al., 2001).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medical Sciences, Institute of Neuroscience, Newcastle University Newcastle-upon-Tyne, UK.

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.

No MeSH data available.


Related in: MedlinePlus