Interaction between native and prosthetic visual responses in optogenetic visual restoration
Eleonora Carpentiero, Steven Hughes, Jessica Rodgers, Nermina Xhaferri, Sumit Biswas, Michael J. Gilhooley, Mark W. Hankins, Moritz Lindner
Eleonora Carpentiero, Steven Hughes, Jessica Rodgers, Nermina Xhaferri, Sumit Biswas, Michael J. Gilhooley, Mark W. Hankins, Moritz Lindner
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Research Article Neuroscience Ophthalmology

Interaction between native and prosthetic visual responses in optogenetic visual restoration

Abstract

Degenerative retinal disorders leading to irreversible photoreceptor death are a common cause of blindness. Optogenetic gene therapy aims to restore vision in affected individuals by introducing light-sensitive opsins into the surviving neurons of the inner retina. While up until now, the main focus of optogenetic therapy has been on terminally blind individuals, treating at stages where residual native vision is present could have several advantages. However, it is still unknown how residual native and optogenetic vision would interact if present at the same time. Using transgenic mice expressing the optogenetic tool ReaChR in ON-bipolar cells, we herein examine this interaction through electroretinography (ERG) and visually evoked potentials (VEP). We find that optogenetic responses show a peculiar ERG signature and are enhanced in retinas without photoreceptor loss. Conversely, native responses are dampened in the presence of ReaChR. Moreover, in VEP recordings, we find that optogenetic responses reach the cortex asynchronous to the native response. These findings should be taken into consideration when planning future clinical trials and may direct future preclinical research to optimize optogenetic approaches for visual restoration. The identified ERG signatures, moreover, may serve to track treatment efficiency in clinical trials.

Authors

Eleonora Carpentiero, Steven Hughes, Jessica Rodgers, Nermina Xhaferri, Sumit Biswas, Michael J. Gilhooley, Mark W. Hankins, Moritz Lindner

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Figure 4

Light-adapted ERG recordings.

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Light-adapted ERG recordings. (A) Representative recordings for increasi...
(A) Representative recordings for increasing flash stimulus energies from WT mice (top, gray); ReaChR-expressing, nondegenerate mice (middle, dark red); and ReaChR-expressing, retina-degenerate mice (bottom, light red). Note the appearance of a potentially novel, putatively ReaChR-driven ERG component, ao. (B and C) Box plots comparing the implicit times for a-waves (measured in WT mice) and ao-waves (measured in ReaChR-expressing, nondegenerate mice) (B) and ao amplitudes in ReaChR-expressing, nondegenerate and ReaChR-expressing, retina-degenerate mice (C) in response to a 100 cd × s/m2 flash. (D and E) Stimulus-response curves for a- and b-wave amplitudes. In D, a-wave amplitudes for ReaChR-expressing, nondegenerate mice were not measured beyond 30 cd × s/m2, as these were superimposed by oscillatory responses following the ao-wave, hindering accurate quantification. The b-wave amplitudes presented in E are measured from baseline/zero potential. The dotted line indicates the “activation threshold” for ReaChR (8 × 1014 photons/cm2/s = 68 cd × s/m2) — i.e., the minimum stimulus energy required to induce a change in spike firing rate as determined in ref. 11. (F) Corresponding summary statistics for b-wave amplitudes at 10 cd × s/m2, where no major ReaChR activation would be expected, and 100 cd × s/m2, where both, native cone-opsins and ReaChR are expected to be activated. (G) The b-wave implicit times for the same stimulus conditions as in F. For comparisons between 2 groups, Student’s t test (2-tailed) was used to test for significance. In case of more than 2 groups, Tukey HSD was used. *P < 0.05. **P < 0.01, ***P < 0.001.