Chromatic vision starts at the retinal photoreceptors but photoreceptors are themselves color-blind, responding only to their effective quantal catch and not to the wavelength of the caught photon per se. Mitchell and Rushton (1971) termed this phenomenon the univariance concept, and it is widely used in designing silent-substitution stimuli to test the unique contributions of specific photoreceptor types to vision. In principle, this procedure controls the effective quantal catch of photoreceptors well and hence works at the phototransduction-cascade level of vision. However, both phototransduction-cascade modulation and the horizontal-cell-mediated feedback signal determine photoreceptor output. Horizontal cells receive input from, and send feedback to, more than one photoreceptor type. This should mean that silentsubstitution stimuli do not silence horizontal-cell activity, and that this activity is fed back to the silenced cones. This in turn will modulate the output of silenced cones, making them not so silent after all. Here we tested this idea and found that silent-substitution stimuli can adequately silence cone-membrane potential responses. However, these cones still received a feedback signal from horizontal cells, which modulates their Ca 2þ current and thus their output. These feedback-induced Ca 2þ-current changes are substantial, as they are of the same order of magnitude as Ca 2þ-current changes that occur when cones are directly stimulated with light. This illustrates that great care needs to be taken in interpreting results obtained with silent-substitution stimuli. In the discussion, we outline two basic types of interpretation pitfalls that can occur.
While no significant measurable differences in K- and E-values were observed, fitting of a pancorneal toric RGP contact lens in keratoconus led to a marked improvement in visual acuity and a visible change in corneal compression.
Biblical references aside, restoring vision to the blind has proven to be a major technical challenge. In recent years, considerable advances have been made towards this end, especially when retinal degeneration underlies the vision loss such as occurs with retinitis pigmentosa. Under these conditions, optogenetic therapies are a particularly promising line of inquiry where remaining retinal cells are made into “artificial photoreceptors”. However, this strategy is not without its challenges and a model system using human retinal explants would aid its continued development and refinement. Here, we cultured post-mortem human retinas and show that explants remain viable for around 7 days. Within this period, the cones lose their outer segments and thus their light sensitivity but remain electrophysiologically intact, displaying all the major ionic conductances one would expect for a vertebrate cone. We optogenetically restored light responses to these quiescent cones using a lentivirus vector constructed to express enhanced halorhodopsin under the control of the human arrestin promotor. In these ‘reactivated’ retinas, we show a light-induced horizontal cell to cone feedback signal in cones, indicating that transduced cones were able to transmit their light response across the synapse to horizontal cells, which generated a large enough response to send a signal back to the cones. Furthermore, we show ganglion cell light responses, suggesting the cultured explant’s condition is still good enough to support transmission of the transduced cone signal over the intermediate retinal layers to the final retinal output level. Together, these results show that cultured human retinas are an appropriate model system to test optogenetic vision restoration approaches and that cones which have lost their outer segment, a condition occurring during the early stages of retinitis pigmentosa, are appropriate targets for optogenetic vision restoration therapies.
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