While the healthy human retina contains ∼1.2 million RGCs, current retinal chips have 16–64 electrodes spaced 100–200 μm

apart (Winter et al., 2007). Chips with electrodes more densely packed exhibit crosstalk between electrodes, limiting their effectiveness. At present, the highest resolution that could be provided by retinal chip stimulation is several orders of magnitude lower than the theoretical limits imposed by RGC density in the macula, the region crucial for high-acuity vision. The area of RGC stimulation is limited by the physical size of the chip implant, which typically covers only the central 20 degrees of vision in the macula (Chader et al., 2009). Larger chips are possible, Venetoclax purchase but there are challenges

in power delivery and achieving stable adherence to the retina. Similar to photoswitches, the spatial resolution conferred by optogenetic tools is defined by the size of the cell type targeted for expressing a given light-activated protein. In principle, the smaller the cell type and the more densely they are packed together, the higher the spatial resolution. In practice, viral transduction with current vectors has resulted in expression of optogenetic tools in a minority of targeted cells (e.g., ∼5% of bipolar cells in mice [Lagali et al., 2008] and 5%–10% of RGCs selleck kinase inhibitor in marmosets [Ivanova et al., 2010]), but it is possible that new viral vectors will be developed that improve transduction efficiency (Vandenberghe et al., 2011). Viral transduction of NpHR has resulted in more efficient transduction (50%–75%) of remnant cones in blind mice (Busskamp et al., 2010), but

this approach is only appropriate for the few patients thought to possess remnant cones. Viral transduction of cones requires subretinal injection, which involves local detachment of a portion of the retina from the underlying retinal pigment epithelium. Effective viral gene transfer is limited to the detached area (Hauswirth et al., 2008). Stem cell approaches offer the potential for greater all spatial resolution, but this is dependent on having a high density of differentiated photoreceptor cells that form functional and anatomically correct synapses with appropriate retinal neuron partners, and at present, only a very low density of cells has been achieved (Lamba et al., 2009). Optogenetic tools have the advantage of being genetically-targetable to particular types of neurons to generate the appropriate stimulation or inhibition of firing, for example to ON- or OFF-RGCs (Busskamp et al., 2010 and Lagali et al., 2008). Moreover, ChR2 and NpHR can be co-expressed in the same RGC and trafficked to different compartments to restore antagonistic center-surround responses (Greenberg et al., 2011).