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

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.

Intravitreal Delivery of Melatonin Is Protective Against the Photoreceptor Loss in Mice: A Potential Therapeutic Strategy for Degenerative Retinopathy

“…Similar to other RP animal models (Masland, 2001), spontaneous RGCs hyperactivity occurs in the MNU administered mice. The spontaneous RGCs hyperactivity is detrimental to the visual signaling, since it would add unnecessary noise into retinal circuits (Marc et al, 2007;Lin et al, 2009;Wu, 2009;Bisti, 2010;Barrett et al, 2015). Melatonin therapy can restrain the spontaneous hyperactivity and enhance the light induced response in MNU administered mice.…”

CoPP-Induced-Induced HO-1 Overexpression Alleviates Photoreceptor Degeneration With Rapid Dynamics: A Therapeutic Molecular Against Retinopathy

“…[43][44][45] As the output neurons of the retina, RGCs collect field potentials from presynaptic inputs and convert them into firing spikes. 46 The success of any therapeutic strategy ultimately depends on the functional recovery of RGCs. 47 CoPP treatment can alter the electrophysiological properties of RGCs, and alleviate the RGC hyperactivity in MNU-administered mice, thereby improving the signaling efficiency.…”

Selective Manipulation of Neural Circuits

“…One promising area for the use of circuit-specific tools is optogenetics for retinal disease [199,200]. In retinitis pigmentosa, for example, photoreceptors are lost.…”