Robust cone-mediated signaling persists late into rod photoreceptor degeneration

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    Evaluation Summary:

    In this study, the authors assess the decline of retinal function in a mouse model of slow photoreceptor degeneration. The authors use a linear-nonlinear receptive field model to characterize functional changes across some RGC populations and information theory to assess the fidelity of RGC signaling. They show remarkable preservation of cone-driven ganglion cell light responses in advanced stages of a retinitis pigmentosa model when most rods have died, and cone morphologies are dramatically altered. The results are presented clearly in the text and figures and are scholarly discussed. However, there are several technical and conceptual concerns with the conclusions that can be drawn.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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Abstract

Rod photoreceptor degeneration causes deterioration in the morphology and physiology of cone photoreceptors along with changes in retinal circuits. These changes could diminish visual signaling at cone-mediated light levels, thereby limiting the efficacy of treatments such as gene therapy for rescuing normal, cone-mediated vision. However, the impact of progressive rod death on cone-mediated signaling remains unclear. To investigate the fidelity of retinal ganglion cell (RGC) signaling throughout disease progression, we used a mouse model of rod degeneration ( Cngb1 neo/neo ). Despite clear deterioration of cone morphology with rod death, cone-mediated signaling among RGCs remained surprisingly robust: spatiotemporal receptive fields changed little and the mutual information between stimuli and spiking responses was relatively constant. This relative stability held until nearly all rods had died and cones had completely lost well-formed outer segments. Interestingly, RGC information rates were higher and more stable for natural movies than checkerboard noise as degeneration progressed. The main change in RGC responses with photoreceptor degeneration was a decrease in response gain. These results suggest that gene therapies for rod degenerative diseases are likely to prolong cone-mediated vision even if there are changes to cone morphology and density.

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  1. Author Response

    Reviewer #1 (Public Review):

    In this study, Scalabrino et al. show persistent cone-mediated RGC signaling despite changes in cone morphology and density with rod degeneration in CNGB1 mouse model of retinitis pigmentosa. The authors use a linear-nonlinear receptive field model to measure functional changes (spatial and temporal filters and gain) across the RGC populations with space-time separable receptive fields. At mesopic and photopic conditions, receptive field changes were minor until rod death exceeded 50%; while response gain decreased with photoreceptor degeneration. Using information theory, the authors evaluated the fidelity of RGC signaling demonstrated that mutual information decreased with rod loss, but cone-mediated RGC signaling was relatively stable and was more robust for natural movies than …

  2. Evaluation Summary:

    In this study, the authors assess the decline of retinal function in a mouse model of slow photoreceptor degeneration. The authors use a linear-nonlinear receptive field model to characterize functional changes across some RGC populations and information theory to assess the fidelity of RGC signaling. They show remarkable preservation of cone-driven ganglion cell light responses in advanced stages of a retinitis pigmentosa model when most rods have died, and cone morphologies are dramatically altered. The results are presented clearly in the text and figures and are scholarly discussed. However, there are several technical and conceptual concerns with the conclusions that can be drawn.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private …

  3. Reviewer #1 (Public Review):

    In this study, Scalabrino et al. show persistent cone-mediated RGC signaling despite changes in cone morphology and density with rod degeneration in CNGB1 mouse model of retinitis pigmentosa. The authors use a linear-nonlinear receptive field model to measure functional changes (spatial and temporal filters and gain) across the RGC populations with space-time separable receptive fields. At mesopic and photopic conditions, receptive field changes were minor until rod death exceeded 50%; while response gain decreased with photoreceptor degeneration. Using information theory, the authors evaluated the fidelity of RGC signaling demonstrated that mutual information decreased with rod loss, but cone-mediated RGC signaling was relatively stable and was more robust for natural movies than artificial stimulus. This …

  4. Reviewer #2 (Public Review):

    In this study, the authors assess the decline of retinal function in a mouse model of slow photoreceptor degeneration - the Cngb1neo/neo. Rod loss occurs between 1-7 months and complete cone loss occurs by 8-9 months. The authors characterize cone loss in the first 7 months and find that 70% of cones are still there at 7 months, though their outer segments are highly degraded. They then use MEA recordings to characterize retinal function using a variety of measures. First, they use spike-triggered averaging to determine the spatial and temporal receptive fields, restricting this analysis to RGCs that have separable spatial and temporal receptive fields. They find that both rod and cone receptive fields are surprisingly intact over the first 5 months, identifying primarily a reduction in contrast response …

  5. Reviewer #3 (Public Review):

    In the manuscript by Scalabrino et al. a rigorous characterization of the functionality of retinal ganglion cells in a mouse model of rod photoreceptor degeneration is presented. The authors analyzed the degeneration of cone photoreceptors, which is known to be linked to rod degeneration. Based on the time course of cone degeneration they investigated the functional properties of retinal ganglion cells aged between 1 month and seven months.

    The most interesting finding is robust preservation of functional properties, as reflected in little changes of the receptive fields (spatial and temporal characteristics) or signaling fidelity/information rate. In contrast to other mouse models, the present one shows no oscillatory activity until a complete loss of cone photoreceptors occurred at an age of nine months.

    Al…

  6. Reviewer #4 (Public Review):

    Scalabrino et al. report the remarkable persistence of cone-driven retinal ganglion cell responses in a mouse model of retinitis pigmentosa (i.e., Cngb1 KO mice). The authors first map the time course of primary rod and secondary cone degeneration in Cngb1 KO mice. Approximately 30% of rods are gone at one month (1M), and all rods are lost by 7M in Cngb1 KO retinas. The cone morphology changes progressively as rods degenerate, cone outer segments shrink and are largely absent by 5M. Cones die between 8-9M. Scalabrino et al. next perform multielectrode array recordings from wild-type and Cngb1 KO retinas from 1M to 5M in mesopic and photopic stimulus conditions. They find that spatiotemporal receptive fields remain relatively stable in the face of photoreceptor degeneration, whereas contrast gain gradually …