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D. Balya, P. S. Lagali, G. Awatramani, T. A. Münch, D. S. Kim, C. L. Cepko, B. Roska; Retinal Repair by Circuit-Specific Intervention With Channelrhodopsin-2 PART II. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4878. doi: https://doi.org/.
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The recent advent of genetically encoded optical neuromodulators, such as channelrhodopsin-2 (ChR2), creates the opportunity for circuit-specific intervention in neurological diseases. One of the diseases most amenable to this approach is retinal degeneration (rd), where the progressive loss of photoreceptors leads to complete and irreversible blindness.
We developed a method to specifically activate the ON pathway at the level of the second-order neurons, the bipolar cells. Here we genetically target a light-activated cation channel, ChR2, selectively to ON bipolar cells of degenerated retinas (rd1) in vivo. Reporter gene function in retinal neurons was assessed using (1) behavioral experiments: light box and optokinetic drum; (2) cortical recordings: visually evoked potentials, (3) extracellular spike recordings with multi-electrode array, and (4) intracellular excitation and inhibition measurements via whole-cell patch-clamp technique.
We show that in the absence of photoreceptors, photosensitive ON bipolar cells induce light-evoked spiking activity in ganglion cells. The rescue of light sensitivity is selective: only circuits that signal light increments are functional. Similar to healthy retinas in rescued retinas we show parallel processing, sustained and transient responses in the time domain, and modification of the information flow by inhibitory circuitry, even center-surround organization. Transmission of the light signals to the visual cortex and light-induced behavioral changes were also observed. The peak of the spatial acuity curve of the treated rd1 mice was slightly higher than the reported values for wild type mice.
Targeting photosensors to second-order retinal neurons is able to restore photosensitivity at the retinal, cortical and behavioral level in one of the most aggressive disease models of retinal degeneration. Although the intensity required for stimulating ChR2 is several orders of magnitude greater than that required to stimulate endogenous photopigments, many of the response properties are conserved. The surprising functional preservation of the inner retinal synapses in our study suggests that targeting optical neuromodulators to second-order retinal neurons might be a feasible strategy to restore retinal function.
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