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

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

Probing retinal function with a multi-layered simulator

International audienc

Probing retinal function with a multi-layered simulator

International audienc

Probing retinal function with a multi-layered simulator

International audienc

Human iPSC differentiation to retinal organoids in response to IGF1 and BMP4 activation is line- and method-dependent

Induced pluripotent stem cell (iPSC)‐derived retinal organoids provide a platform to study human retinogenesis, disease modeling, and compound screening. Although retinal organoids may represent tissue structures with greater physiological relevance to the in vivo human retina, their generation is not without limitations. Various protocols have been developed to enable development of organoids with all major retinal cell types; however, variability across iPSC lines is often reported. Modulating signaling pathways important for eye formation, such as those involving bone morphogenetic protein 4 (BMP4) and insulin‐like growth factor 1 (IGF1), is a common approach used for the generation of retinal tissue in vitro. We used three human iPSC lines to generate retinal organoids by activating either BMP4 or IGF1 signaling and assessed differentiation efficiency by monitoring morphological changes, gene and protein expression, and function. Our results showed that the ability of iPSC to give rise to retinal organoids in response to IGF1 and BMP4 activation was line‐ and method‐dependent. This demonstrates that careful consideration is needed when choosing a differentiation approach, which would also depend on overall project aims

Probing retinal function with a multi-layered simulator

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The effect of retinal GABA Depletion by Allylglycineon mouse retinal ganglion cell responses to light

International audienceThe inhibitory neurotransmitter GABA (γ-aminobutyric acid) is metabolized by glutamic acid decarboxylase (GAD) which exists in two iso-forms in the mature CNS, GAD65 and GAD67. Allylglycine, a glycine derivative, is a nonspecific inhibitor of both GAD isoforms. Prolongedexposure to allylgycine can therefore deplete the tissue of endogenous GABA over time (Orlowski et al, 1977; Chabrol et al., 2012). Herewe applied Allylglycine (ALLYL) in vitro over several hours to gradually deplete GABA in the adult mouse retina and compared the effectsof GABA depletion on retinal ganglion cells (RGCs) receptive fields with those obtained by simultaneously blocking all GABAergic recep-tors (type A, B and C)

Analysis of spontaneous activity patterns in developing retina: algorithms and results

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Changing dynamics of spontaneous waves during retinal development: a novel panretinal perspective achieved with the Active Pixel Sensor (APS) 4,096 electrodes array

The developing retina exhibits spontaneous waves of activity spreading across the ganglion cell layer. These waves are present only during a limited perinatal period, and they are known to play important roles during the wiring of visual connections. Using the APS MEA devices consisting of 4,096 electrodes recording at near cellular resolution, we have been able to achieve panretinal recordings of retinal waves in the neonatal mouse retina. We found that the spatiotemporal patterns of the waves undergo profound developmental changes as retinal synaptic networks mature, switching from slow random events propagating over large retinal areas to faster, spatially more restricted events, following several clear repetitive, non-random propagation patterns. This novel panretinal perspective of wave dynamics provides new clues about the role played by retinal waves during visual map formation

Carbon Nanotube Electrodes for Effective Interfacing with Retinal Tissue

We have investigated the use of carbon nanotube coated microelectrodes as an interface material for retinal recording and stimulation applications. Test devices were micro-fabricated and consisted of 60, 30 μm diameter electrodes at spacing of 200 μm. These electrodes were coated via chemical vapor deposition of carbon nanotubes, resulting in conducting, three dimensional surfaces with a high interfacial area. These attributes are important both for the quality of the cell-surface coupling as well as for electro-chemical interfacing efficiency. The entire chip was packaged to fit a commercial multielectrode recording and stimulation system. Electrical recordings of spontaneous spikes from whole-mount neonatal mouse retinas were consistently obtained minutes after retinas were placed over the electrodes, exhibiting typical bursting and propagating waves. Most importantly, the signals obtained with carbon nanotube electrodes have exceptionally high signal to noise ratio, reaching values as high as 75. Moreover, spikes are marked by a conspicuous gradual increase in amplitude recorded over a period of minutes to hours, suggesting improvement in cell-electrode coupling. This phenomenon is not observed in conventional commercial electrodes. Electrical stimulation using carbon nanotube electrodes was also achieved. We attribute the superior performances of the carbon nanotube electrodes to their three dimensional nature and the strong neuro-carbon nanotube affinity. The results presented here show the great potential of carbon nanotube electrodes for retinal interfacing applications. Specifically, our results demonstrate a route to achieve a reduction of the electrode down to few micrometers in order to achieve high efficacy local stimulation needed in retinal prosthetic devices