Dampening Spontaneous Activity Improves the Light Sensitivity and Spatial Acuity of Optogenetic Retinal Prosthetic Responses

Abstract

Retinitis pigmentosa is a progressive retinal dystrophy that causes irreversible visual impairment and blindness. Retinal prostheses currently represent the only clinically available vision-restoring treatment, but the quality of vision returned remains poor. Recently, it has been suggested that the pathological spontaneous hyperactivity present in dystrophic retinas may contribute to the poor quality of vision returned by retinal prosthetics by reducing the signal-to-noise ratio of prosthetic responses. Here, we investigated to what extent blocking this hyperactivity can improve optogenetic retinal prosthetic responses. We recorded activity from channelrhodopsin-expressing retinal ganglion cells in retinal wholemounts in a mouse model of retinitis pigmentosa. Sophisticated stimuli, inspired by those used in clinical visual assessment, were used to assess light sensitivity, contrast sensitivity and spatial acuity of optogenetic responses; in all cases these were improved after blocking spontaneous hyperactivity using meclofenamic acid, a gap junction blocker. Our results suggest that this approach significantly improves the quality of vision returned by retinal prosthetics, paving the way to novel clinical applications. Moreover, the improvements in sensitivity achieved by blocking spontaneous hyperactivity may extend the dynamic range of optogenetic retinal prostheses, allowing them to be used at lower light intensities such as those encountered in everyday life.

Optogenetic restoration of retinal ganglion cell activity in the living primate

“…This is critical because spontaneous hyperactivity 17,18 and structural remodeling 19 have been reported in the inner retina following photoreceptor loss. Understanding how these changes alter restored function and how to mitigate them 20 is crucially important to all vision restoration therapies. The combination of optogenetic stimulation, functional readout in the intact eye, and the ability to cause localized acute damage now makes these studies possible in primates.…”

Development of visual Neuroprostheses: trends and challenges

“…Optogenetic tools (Nagel et al, 2003) have the potential to bypass many of the limitations of electrical stimulation (Delbeke et al, 2017). This technique has been validated in blind animal models of Retinitis Pigmentosa (Sahel & Roska, 2013) and is moving towards human trials for retinal prosthesis (Sahel et al, 2015;Tung et al, 2016;Sengupta et al, 2016;Barrett et al, 2016). The power of optogenetics is that specific neural sub-circuits can be targeted using gene therapy to express the light-sensitive ion channels, and high fidelity control of neural firing can be achieved.…”

Clinical Impact of Spontaneous Hyperactivity in Degenerating Retinas: Significance for Diagnosis, Symptoms, and Treatment

“…To the extent that RGC hyperactivity plays a critical role in establishing retinal and central circuits for visual processing during an early developmental period, its emergence as retinal degenerations progress may help explain the considerably greater effectiveness of treatments such as gene therapy in young children vs. adults ( Maguire et al, 2009 ; Ashtari et al, 2015 ). Direct modulation of RGC hyperactivity – perhaps as a primary therapy, or as a complementary adjunctive treatment – might improve outcomes and/or delay disease ( Toychiev et al, 2013 ; Barrett et al, 2015 , 2016 ). Cutting-edge treatments such as electrical stimulation via a visual prosthesis ( Weiland et al, 2016 ; Cheng et al, 2017 ; Mills et al, 2017 ) may allow very specific modulation of RGC activity so as to counteract excessive “random noise,” and/or fine tune the complex signals that encode visual information sent to the brain ( Sekirnjak et al, 2008 ; Freeman et al, 2011 ; Nirenberg and Pandarinath, 2012 ; Jepson et al, 2014 ; Im and Fried, 2015 ).…”