-
Documenta Ophthalmologica. Advances in...The impact of a disease on phototransduction can be assessed by fitting the leading edge of the rod a-wave to high-energy flashes with a quantitative expression. Two... (Review)
Review
The impact of a disease on phototransduction can be assessed by fitting the leading edge of the rod a-wave to high-energy flashes with a quantitative expression. Two parameters of rod receptor activity are obtained, S (sensitivity) and Rm (maximum response). In this study, the meaning of these parameters and examples of conditions that change them were examined. In addition, a new protocol was developed for obtaining these parameters. A set of three to five white flashes were first presented in the dark and then on an adapting field (30 cd/m2). Subtracting the light-adapted responses from the dark-adapted responses yielded isolated rod a-wave responses. A clinical protocol was developed based on a single white flash energy. It is possible to determine whether a disease is producing a change in S and/or Rm with this single flash energy without the use of any equations.
Topics: Electroretinography; Humans; Models, Biological; Photic Stimulation; Retinal Rod Photoreceptor Cells
PubMed: 9476593
DOI: 10.1007/BF02584080 -
Progress in Retinal and Eye Research Mar 2014The a-wave of the electroretinogram (ERG) reflects the response of photoreceptors to light, but what determines the exact waveform of the recorded voltage is not... (Review)
Review
The a-wave of the electroretinogram (ERG) reflects the response of photoreceptors to light, but what determines the exact waveform of the recorded voltage is not entirely understood. We have now simulated the trans-retinal voltage generated by the photocurrent of dark-adapted mammalian rods, using an electrical model based on the in vitro measurements of Hagins et al. (1970) and Arden (1976) in rat retinas. Our simulations indicate that in addition to the voltage produced by extracellular flow of photocurrent from rod outer to inner segments, a substantial fraction of the recorded a-wave is generated by current that flows in the outer nuclear layer (ONL) to hyperpolarize the rod axon and synaptic terminal. This current includes a transient capacitive component that contributes an initial negative "nose" to the trans-retinal voltage when the stimulus is strong. Recordings in various species of the a-wave, including the peak and initial recovery towards the baseline, are consistent with simulations showing an initial transient primarily related to capacitive currents in the ONL. Existence of these capacitive currents can explain why there is always a substantial residual transient a-wave when post-receptoral responses are pharmacologically inactivated in rodents and nonhuman primates, or severely genetically compromised in humans (e.g. complete congenital stationary night blindness) and nob mice. Our simulations and analysis of ERGs indicate that the timing of the leading edge and peak of dark-adapted a-waves evoked by strong stimuli could be used in a simple way to estimate rod sensitivity.
Topics: Animals; Dark Adaptation; Electroretinography; Mammals; Models, Theoretical; Retinal Rod Photoreceptor Cells
PubMed: 24355774
DOI: 10.1016/j.preteyeres.2013.12.003 -
Pflugers Archiv : European Journal of... Sep 2021Rod and cone photoreceptors of the vertebrate retina utilize cGMP as the primary intracellular messenger for the visual signaling pathway that converts a light stimulus... (Review)
Review
Rod and cone photoreceptors of the vertebrate retina utilize cGMP as the primary intracellular messenger for the visual signaling pathway that converts a light stimulus into an electrical response. cGMP metabolism in the signal-transducing photoreceptor outer segment reflects the balance of cGMP synthesis (catalyzed by guanylyl cyclase) and degradation (catalyzed by the photoreceptor phosphodiesterase, PDE6). Upon light stimulation, rapid activation of PDE6 by the heterotrimeric G-protein (transducin) triggers a dramatic drop in cGMP levels that lead to cell hyperpolarization. Following cessation of the light stimulus, the lifetime of activated PDE6 is also precisely regulated by additional processes. This review summarizes recent advances in the structural characterization of the rod and cone PDE6 catalytic and regulatory subunits in the context of previous biochemical studies of the enzymological properties and allosteric regulation of PDE6. Emphasis is given to recent advances in understanding the structural and conformational changes underlying the mechanism by which the activated transducin α-subunit binds to-and relieves inhibition of-PDE6 catalysis that is controlled by its intrinsically disordered, inhibitory γ-subunit. The role of the regulator of G-protein signaling 9-1 (RGS9-1) in regulating the lifetime of the transducin-PDE6 is also briefly covered. The therapeutic potential of pharmacological compounds acting as inhibitors or activators targeting PDE6 is discussed in the context of inherited retinal diseases resulting from mutations in rod and cone PDE6 genes as well as other inherited defects that arise from excessive cGMP accumulation in retinal photoreceptor cells.
Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 6; Humans; Protein Structure, Secondary; Protein Structure, Tertiary; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Vision, Ocular
PubMed: 33860373
DOI: 10.1007/s00424-021-02562-x -
Investigative Ophthalmology & Visual... Jun 2016Preclinical studies on photoreceptor transplantation provided evidence for restoration of visual function with pluripotent stem cells considered as a potential source...
PURPOSE
Preclinical studies on photoreceptor transplantation provided evidence for restoration of visual function with pluripotent stem cells considered as a potential source for sufficient amounts of donor material. Adequate preclinical models representing retinal disease conditions of potential future patients are needed for translation research. Here we compared transplant integration in mouse models with mild (prominin1-deficient; Prom1-/-) or severe (cone photoreceptor function loss 1/rhodopsin-deficient double-mutant; Cpfl1/Rho-/-) cone-rod degeneration.
METHODS
For photoreceptor transplant production, we combined the mouse embryonic stem cell retinal organoid system with rhodopsin-driven GFP cell labeling by recombinant adeno-associated virus (AAV). Organoid-derived photoreceptors were enriched by CD73-based magnetic-activated cell sorting (MACS) and transplanted subretinally into wild-type, Prom1-/- and Cpfl1/Rho-/- hosts. The survival, maturation, and synapse formation of donor cells was analyzed by immunohistochemistry.
RESULTS
Retinal organoids yielded high photoreceptor numbers that were further MACS-enriched to 85% purity. Grafted photoreceptors survived in the subretinal space of all mouse models. Some cells integrated into wild-type as well as Prom1-/- mouse retinas and acquired a mature morphology, expressing rod and synaptic markers in close proximity to second-order neurons. In contrast, in the novel Cpfl1/Rho-/- model with complete photoreceptor degeneration, transplants remained confined to the subretinal space, expressed rod-specific but only reduced synaptic markers, and did not acquire mature morphology.
CONCLUSIONS
Comparison of photoreceptor grafts in preclinical models with incomplete or complete photoreceptor loss, showed differential transplant success with effective and impaired integration, respectively. Thus, Cpfl1/Rho-/- mice represent a potential benchmark model resembling patients with severe retinal degeneration to optimize photoreceptor replacement therapies.
Topics: Animals; Cone-Rod Dystrophies; Disease Models, Animal; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Knockout; Retinal Degeneration; Retinal Rod Photoreceptor Cells; Stem Cell Transplantation; Stem Cells
PubMed: 27367586
DOI: 10.1167/iovs.16-19087 -
Nature Medicine Feb 2000
Topics: Animals; Diltiazem; Mice; Mice, Mutant Strains; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa
PubMed: 10655077
DOI: 10.1038/72170 -
The Journal of Neuroscience : the... Aug 2021Epigenetic modifiers are increasingly being investigated as potential therapeutics to modify and overcome disease phenotypes. Diseases of the nervous system present a...
Epigenetic modifiers are increasingly being investigated as potential therapeutics to modify and overcome disease phenotypes. Diseases of the nervous system present a particular problem as neurons are postmitotic and demonstrate relatively stable gene expression patterns and chromatin organization. We have explored the ability of epigenetic modifiers to prevent degeneration of rod photoreceptors in a mouse model of retinitis pigmentosa (RP), using rd10 mice of both sexes. The histone modification eraser enzymes lysine demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1) are known to have dramatic effects on the development of rod photoreceptors. In the RP mouse model, inhibitors of these enzymes blocked rod degeneration, preserved vision, and affected the expression of multiple genes including maintenance of rod-specific transcripts and downregulation of those involved in inflammation, gliosis, and cell death. The neuroprotective activity of LSD1 inhibitors includes two pathways. First, through targeting histone modifications, they increase accessibility of chromatin and upregulate neuroprotective genes, such as from the Wnt pathway. We propose that this process is going in rod photoreceptors. Second, through nonhistone targets, they inhibit transcription of inflammatory genes and inflammation. This process is going in microglia, and lack of inflammation keeps rod photoreceptors alive. Retinal degenerations are a leading cause of vision loss. RP is genetically very heterogeneous, and the multiple pathways leading to cell death are one reason for the slow progress in identifying suitable treatments for patients. Here we demonstrate that inhibition of LSD1and HDAC1 in a mouse model of RP leads to preservation of rod photoreceptors and visual function, retaining of expression of rod-specific genes, and with decreased inflammation, cell death, and Müller cell gliosis. We propose that these epigenetic inhibitors cause more open and accessible chromatin, allowing expression of neuroprotective genes. A second mechanism that allows rod photoreceptor survival is suppression of inflammation by epigenetic inhibitors in microglia. Manipulation of epigenetic modifiers is a new strategy to fight neurodegeneration in RP.
Topics: Animals; Cell Death; Disease Models, Animal; Epigenesis, Genetic; Female; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Histone Demethylases; Male; Mice; Mice, Inbred C57BL; Nerve Degeneration; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Tranylcypromine
PubMed: 34193554
DOI: 10.1523/JNEUROSCI.3102-20.2021 -
Optics Letters Sep 2020Noninvasive, objective measurement of rod function is as significant as that of cone function, and for retinal diseases such as retinitis pigmentosa and age-related...
Noninvasive, objective measurement of rod function is as significant as that of cone function, and for retinal diseases such as retinitis pigmentosa and age-related macular degeneration, rod function may be a more sensitive biomarker of disease progression and efficacy of treatment than cone function. Functional imaging of single human rod photoreceptors, however, has proven difficult because their small size and rapid functional response pose challenges for the resolution and speed of the imaging system. Here, we describe light-evoked, functional responses of human rods and cones, measured noninvasively using a synchronized adaptive optics optical coherence tomography (OCT) and scanning light ophthalmoscopy (SLO) system. The higher lateral resolution of the SLO images made it possible to confirm the identity of rods in the corresponding OCT volumes.
Topics: Humans; Light; Ophthalmoscopy; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells
PubMed: 32870829
DOI: 10.1364/OL.398868 -
Advances in Experimental Medicine and... 2012
Topics: Dark Adaptation; Databases, Factual; Electroretinography; Humans; Macular Degeneration; Recovery of Function; Retinal Degeneration; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Stargardt Disease; Vision, Ocular
PubMed: 22183369
DOI: 10.1007/978-1-4614-0631-0_62 -
Advances in Experimental Medicine and... 2008The zebrafish is an excellent model organism in which to study the retina's response to photoreceptor degeneration and/or acute injury. While much has been learned about... (Review)
Review
The zebrafish is an excellent model organism in which to study the retina's response to photoreceptor degeneration and/or acute injury. While much has been learned about the retinal stem and progenitor cells that mediate the damage response, several questions remain that cannot be addressed by acute models of injury. The development of genetic models, such as the XOPS-mCFP transgenic line, should further efforts to understand the nature of the signals that promote rod progenitor proliferation and differentiation following photoreceptor loss. This in turn may help to refine future approaches in higher vertebrates aimed at enhancing retinal progenitor cell activity for therapeutic purposes.
Topics: Animals; Models, Biological; Retina; Retinal Rod Photoreceptor Cells; Stem Cells; Zebrafish
PubMed: 18188965
DOI: 10.1007/978-0-387-74904-4_42 -
Cell Communication and Signaling : CCS Oct 2014The rod photoreceptor cGMP-gated cation channel, consisting of three α- and one β subunit, controls ion flow into the rod outer segment (ROS). In addition to the...
BACKGROUND
The rod photoreceptor cGMP-gated cation channel, consisting of three α- and one β subunit, controls ion flow into the rod outer segment (ROS). In addition to the β-subunit, the Cngb1 locus encodes an abundant soluble protein, GARP2 that binds stoichiometrically to rod photoreceptor cGMP phosphodiesterase type 6 (PDE6). To examine the in vivo functional role of GARP2 we generated opsin promoter-driven transgenic mice overexpressing GARP2 three-fold specifically in rod photoreceptors.
RESULTS
In the GARP2 overexpressing transgenic mice (tg), the endogenous channel β-subunit, cGMP phosphodiesterase α-subunit, peripherin2/RDS and guanylate cyclase I were present at WT levels and were properly localized within the ROS. While localized properly within ROS, two proteins cGMP phosphodiesterase α-subunit (1.4-fold) and cGMP-gated cation channel α-subunit (1.2-fold) were moderately, but significantly elevated. Normal stratification of all retinal layers was observed, and ROS were stable in numbers but were 19% shorter than WT. Analysis of the photoresponse using electroretinography (ERG) showed that tg mice exhibit no change in sensitivity indicating overall normal rod function, however two parameters of the photoresponse significantly differed from WT responses. Fitting of the rising phase of the ERG a-wave to an accepted model of phototransduction showed a two-fold increase in phototransduction gain in the tg mice. The increase in gain was confirmed in isolated retinal tissue and by suction electrode recordings of individual rod photoreceptor cells. A measure of response recovery, the dominant time constant (τD) was elevated 69% in isolated retina compared to WT, indicating slower shutoff of the photoresponse.
CONCLUSIONS
GARP2 may participate in regulating visual signal transduction through a previously unappreciated role in regulating phototransduction gain and recovery.
Topics: Animals; Electroretinography; Membrane Proteins; Mice, Inbred C57BL; Mice, Transgenic; Retinal Rod Photoreceptor Cells
PubMed: 25323447
DOI: 10.1186/s12964-014-0067-5