Local photoreceptor degeneration causes local pathophysiological remodeling of retinal neurons

Denlinger, Bristol; Helft, Zachary; Telias, Michael; Lorach, Henri; Palanker, Daniel; Krämer, Richard

doi:10.1172/jci.insight.132114

Cited by 28 publications

(34 citation statements)

References 29 publications

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“…Our studies have demonstrated that RA/RAR-signaling is necessary and sufficient to explain two critical and early aspects of remodeling in RGCs: hyperactivity and hyperpermeability (Tochitsky et al, 2016;Telias et al, 2019;Denlinger et al, 2020). Using mouse models for fast and slow RP (rd1 and rd10, respectively), we found that photoreceptor degeneration is directly associated with a P2X-dependent increase in RGCs membrane permeability.…”

Section: Retinoic Acid-dependent Signaling Is Essential For Remodelingmentioning

confidence: 67%

“…Functional abnormalities across outer and inner retinal circuits include changes in synaptic transmission and electrical coupling among similar and different neuronal subtypes, as well as persistent spontaneous oscillations and retinal waves (Marc et al, 2007;Lin et al, 2012b;Euler and Schubert, 2015). RGCs develop intrinsic spontaneous hyperactivity and cell membrane hyperpermeability (Tochitsky et al, 2016;Telias et al, 2019;Denlinger et al, 2020). These structural and functional abnormalities observed during remodeling do not happen in unison across the degenerating retina.…”

Section: Downstream Effects Of Photoreceptor Degenerationmentioning

confidence: 99%

“…These structural and functional abnormalities observed during remodeling do not happen in unison across the degenerating retina. Changes such as neuronal hyperactivity and enhanced membrane hyperpermeability can be observed as soon as days or weeks upon degeneration onset in mice and rat models of RP and AMD (Tochitsky et al, 2016;Telias et al, 2019;Denlinger et al, 2020), while structural changes and the disruption of cell layers happen only upon prolonged degeneration of many weeks to months (Garcia-Ayuso et al, 2019;Pfeiffer et al, 2020). Collectively, functional remodeling results in a "noisy" retina, obscuring remaining light-responses and reducing signal fidelity in treatments aimed at restoring vision (Barrett et al, 2015;Stasheff, 2018).…”

Section: Downstream Effects Of Photoreceptor Degenerationmentioning

confidence: 99%

“…Whatever mechanism delivers RA to RGCs, the resulting remodeling is stereotypical and found in RGCs of mice and rat models of RP (Tochitsky et al, 2016;Telias et al, 2019), as well as in a rat model of AMD (Denlinger et al, 2020). In RP mice, degeneration-dependent spontaneous hyperactivity obscures remaining light responses, and blocking RAR activation in vivo improves light sensitivity and visual perception (Telias et al, 2019).…”

Section: Retinoic Acid-dependent Signaling Is Essential For Remodelingmentioning

confidence: 99%

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Degeneration-Dependent Retinal Remodeling: Looking for the Molecular Trigger

2020

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Vision impairment and blindness in humans are most frequently caused by the degeneration and loss of photoreceptor cells in the outer retina, as is the case for age-related macular degeneration, retinitis pigmentosa, retinal detachment and many other diseases. While inner retinal neurons survive degeneration, they undergo fundamental pathophysiological changes, collectively known as “remodeling.” Inner retinal remodeling downstream to photoreceptor death occurs across mammalian retinas from mice to humans, independently of the cause of degeneration. It results in pervasive spontaneous hyperactivity and membrane hyperpermeability in retinal ganglion cells, which funnel all retinal signals to the brain. Remodeling reduces light detection in vision-impaired patients and precludes meaningful vision restoration in blind individuals. In this review, we summarize current hypotheses proposed to explain remodeling and their potential medical significance highlighting the important role played by retinoic acid and its receptor.

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Section: Retinoic Acid-dependent Signaling Is Essential For Remodelingmentioning

confidence: 67%

Section: Downstream Effects Of Photoreceptor Degenerationmentioning

confidence: 99%

Section: Downstream Effects Of Photoreceptor Degenerationmentioning

confidence: 99%

Section: Retinoic Acid-dependent Signaling Is Essential For Remodelingmentioning

confidence: 99%

See 2 more Smart Citations

Degeneration-Dependent Retinal Remodeling: Looking for the Molecular Trigger

2020

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“…Hyperactivation of retinal ganglion cells was recently demonstrated in the retina of rodents undergoing photoreceptor degeneration. 31,32 Future studies with a larger cohort of patients with RP at various disease stages may shed more light on these findings.…”

Section: Discussionmentioning

confidence: 97%

Chromatic Pupilloperimetry Measures Correlate With Visual Acuity and Visual Field Defects in Retinitis Pigmentosa Patients

Sher

Tucker

Gurevich

et al. 2020

Trans. Vis. Sci. Tech.

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To evaluate the ability of chromatic pupilloperimetry to identify visual field (VF) defects in patients with retinitis pigmentosa (RP) and to test the correlation between pupilloperimetry impairment and retinal structural and functional measures. Methods: The pupil responses of 10 patients with RP (mean age, 41.3 ± 16.2 years) and 32 healthy age-similar controls (mean age, 50.7 ± 15.5 years) for 54 focal blue and red stimuli presented in a 24-2 VF were recorded. The pupilloperimetry measures were correlated with Humphrey VF mean deviation, best-corrected visual acuity, and ellipsoid zone area. Results: Substantially lower percentage of pupil contraction and maximal pupil contraction velocity (MCV) were recorded in patients with RP throughout the VF in response to blue and red stimuli. The mean absolute deviation (MADEV) in the latency of MCV (LMCV) was significantly larger in patients compared with controls for blue and red stimuli (P = 1.0 × 10 −7 and P = 1.0 × 10 −6 , respectively). The LMCV MADEV differentiated between patients and controls with high specificity and sensitivity (area under the receiver operating characteristic curve, 0.987 and 0.973 for blue and red, respectively). The MADEV of LMCV for blue stimuli correlated with best-corrected visual acuity (ρ = 0.938, P = 5.9 × 10 −5) and ellipsoid zone area (ρ = −0.857; P = 0.002). The MADEV of LMCV for red stimuli correlated with Humphrey VF mean deviation (ρ = −0.709; P = 0.022). Minimizing the test to 15 targets maintained a diagnosis of retinal damage in patients with RP with high sensitivity and specificity (area under the receiver operating characteristic curve, 0.927). Conclusions: The chromatic pupilloperimetry measures significantly correlated with retinal function and structure in patients with RP at various disease stages. Translational Relevance: Chromatic pupilloperimetry may enable objective assessment of visual field defects and visual acuity in RP.

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Cyclodextrin‐Assisted Delivery of Azobenzene Photoswitches for Uniform and Long‐Term Restoration of Light Responses in Degenerated Retinas of Blind Mice

Cao

Lyons

Smith

et al. 2021

Advanced Therapeutics

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Azobenzene photoswitches are promising drug candidates for bestowing light sensitivity onto retinal neurons after photoreceptors degenerate in blinding disorders such as retinitis pigmentosa (RP). A potent photoswitch, BENAQ, targets a subset of retinal ganglion cells (RGCs), interacting with voltage‐gated ion channels to enable light‐triggered action potential firing. In mouse models of RP, injection of BENAQ into the vitreous of the eye photosensitizes RGCs to non‐damaging wavelengths and intensities of light. While the concentration required to elicit light responses is non‐toxic, effective drug delivery to the retina in vivo has remained a serious challenge. BENAQ aggregates near the injection site, causing non‐uniform photosensitization with a half‐life of 7 days, too transient for therapeutic vision restoration. Here, cyclodextrins are used to encapsulate BENAQ via host–guest chemistry to increase solubility and improve retinal delivery. SBE‐CD, a sulfobutylether β‐cyclodextrin, envelops the aromatic moieties of BENAQ to form a stable complex that dramatically enhances photosensitization, prolonging light responses to a half‐life of 31 days. SBE‐CD also ensures dispersal of BENAQ, resulting in uniform photosensitization across the retina. Hence the host–guest interaction between SBE‐CD and BENAQ overcomes limitations of intraocular delivery, guiding how photoswitches may be formulated as a possible treatment for human blindness.

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Local photoreceptor degeneration causes local pathophysiological remodeling of retinal neurons

Cited by 28 publications

References 29 publications

Degeneration-Dependent Retinal Remodeling: Looking for the Molecular Trigger

Degeneration-Dependent Retinal Remodeling: Looking for the Molecular Trigger

Chromatic Pupilloperimetry Measures Correlate With Visual Acuity and Visual Field Defects in Retinitis Pigmentosa Patients

Cyclodextrin‐Assisted Delivery of Azobenzene Photoswitches for Uniform and Long‐Term Restoration of Light Responses in Degenerated Retinas of Blind Mice

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