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Biomedicine & Pharmacotherapy =... Jun 2020Photoreceptor cells are first-order retinal neurons that directly contribute to the formation of vision. Photoreceptor degeneration is the primary cause of vision...
Photoreceptor cells are first-order retinal neurons that directly contribute to the formation of vision. Photoreceptor degeneration is the primary cause of vision impairment during the course of retinopathies such as retinitis pigmentosa and age-related macular degeneration, for which photoreceptor-targeted therapies are currently unavailable. Shihu Yeguang Pill (SYP), a classic formula in traditional Chinese medicine, has a long histology of clinical application for the treatment of a wide range of retinopathies in China. However, whether SYP is pharmacological effective at protecting photoreceptor cells is unclear. The current study thus directly addressed the pharmacological implications of SYP in photoreceptor degeneration in a mouse model characterized by bright light-induced retinal degeneration. Non-invasive full-retinal assessment was carried out to evaluate the effect of SYP on the retinal structure and function through optical coherence tomography and electroretinography, respectively. In addition, photoreceptor apoptosis, second-order neuron impairment and reactive changes in retinal microglial and müller cells, hallmark pathologies associated with photoreceptor degeneration, were assessed using immunohistochemistry and real-time PCR analyses. The results showed that SYP treatment attenuated bright light-induced impairment of the retinal structure and function. Moreover, SYP treatment suppressed photoreceptor apoptosis, alleviated the impairment of bipolar and horizontal cells and mitigated the reactive changes of müller and microglial cells in the bright light-exposed retinas. Real-time PCR analyses showed that dysregulated expression of pro-apoptotic c-fos and c-jun and anti-apoptotic bcl-2 as well as proinflammatory TNF-α in the bright light-exposed retinas was partially normalized as a result of SYP treatment. In summary, the work here demonstrates for the first time that SYP treatment protects the retinas from developing bright light-induced photoreceptor degeneration and associated alterations in second-order neurons and glial cells. The findings here thus provide experimental evidence to better support the mechanism-guided clinical application of SYP in the treatment of related retinal degenerative diseases.
Topics: Animals; Apoptosis; Drugs, Chinese Herbal; Electroretinography; Female; Light; Medicine, Chinese Traditional; Mice, Inbred BALB C; Photoreceptor Cells; Photoreceptor Cells, Vertebrate; Retina; Retinal Degeneration
PubMed: 32135462
DOI: 10.1016/j.biopha.2020.110050 -
Molecular Neurobiology Dec 2007The ribbon synapse is a specialized structure that allows photoreceptors to sustain the continuous release of vesicles for hours upon hours and years upon years but also... (Review)
Review
The ribbon synapse is a specialized structure that allows photoreceptors to sustain the continuous release of vesicles for hours upon hours and years upon years but also respond rapidly to momentary changes in illumination. Light responses of cones are faster than those of rods and, mirroring this difference, synaptic transmission from cones is also faster than transmission from rods. This review evaluates the various factors that regulate synaptic kinetics and contribute to kinetic differences between rod and cone synapses. Presynaptically, the release of glutamate-laden synaptic vesicles is regulated by properties of the synaptic proteins involved in exocytosis, influx of calcium through calcium channels, calcium release from intracellular stores, diffusion of calcium to the release site, calcium buffering, and extrusion of calcium from the cytoplasm. The rate of vesicle replenishment also limits the ability of the synapse to follow changes in release. Post-synaptic factors include properties of glutamate receptors, dynamics of glutamate diffusion through the cleft, and glutamate uptake by glutamate transporters. Thus, multiple synaptic mechanisms help to shape the responses of second-order horizontal and bipolar cells.
Topics: Animals; Calcium Channels; Evoked Potentials; Exocytosis; Glutamic Acid; Kinetics; Mammals; Photoreceptor Cells; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Synapses; Synaptic Transmission
PubMed: 17955196
DOI: 10.1007/s12035-007-0019-9 -
Acta Neuropathologica Communications Jan 2021Accumulation of misfolded host proteins is central to neuropathogenesis of numerous human brain diseases including prion and prion-like diseases. Neurons of retina are...
Accumulation of misfolded host proteins is central to neuropathogenesis of numerous human brain diseases including prion and prion-like diseases. Neurons of retina are also affected by these diseases. Previously, our group and others found that prion-induced retinal damage to photoreceptor cells in mice and humans resembled pathology of human retinitis pigmentosa caused by mutations in retinal proteins. Here, using confocal, epifluorescent and electron microscopy we followed deposition of disease-associated prion protein (PrPSc) and its association with damage to critical retinal structures following intracerebral prion inoculation. The earliest time and place of retinal PrPSc deposition was 67 days post-inoculation (dpi) on the inner segment (IS) of cone photoreceptors. At 104 and 118 dpi, PrPSc was associated with the base of cilia and swollen cone inner segments, suggesting ciliopathy as a pathogenic mechanism. By 118 dpi, PrPSc was deposited in both rods and cones which showed rootlet damage in the IS, and photoreceptor cell death was indicated by thinning of the outer nuclear layer. In the outer plexiform layer (OPL) in uninfected mice, normal host PrP (PrPC) was mainly associated with cone bipolar cell processes, but in infected mice, at 118 dpi, PrPSc was detected on cone and rod bipolar cell dendrites extending into ribbon synapses. Loss of ribbon synapses in cone pedicles and rod spherules in the OPL was observed to precede destruction of most rods and cones over the next 2-3 weeks. However, bipolar cells and horizontal cells were less damaged, indicating high selectivity among neurons for injury by prions. PrPSc deposition in cone and rod inner segments and on the bipolar cell processes participating in ribbon synapses appear to be critical early events leading to damage and death of photoreceptors after prion infection. These mechanisms may also occur in human retinitis pigmentosa and prion-like diseases, such as AD.
Topics: Animals; Cell Death; Disease Progression; Mice; Microscopy, Confocal; Microscopy, Electron; Microscopy, Fluorescence; Photoreceptor Connecting Cilium; PrPSc Proteins; Retinal Bipolar Cells; Retinal Cone Photoreceptor Cells; Retinal Photoreceptor Cell Inner Segment; Retinal Photoreceptor Cell Outer Segment; Retinal Rod Photoreceptor Cells; Scrapie
PubMed: 33509294
DOI: 10.1186/s40478-021-01120-x -
Vision Research Mar 2021The skate retina provides a native all-rod retina suited for investigating a single type of photoreceptor regarding its properties and signaling to second order cells....
The skate retina provides a native all-rod retina suited for investigating a single type of photoreceptor regarding its properties and signaling to second order cells. Using the aspartate-induced isolated A-wave of the skate eyecup electroretinogram (ERG), it has been shown that adaptation in rods remains Weber-Fechner-like over a 6-log unit increase in background light intensity. Zinc, which can block calcium channels, has been found in the rod synaptic terminal and the synaptic cleft. Histidine is a zinc chelator. Voltage signals from neurons post-synaptic to rods indicate that histidine increases the dark release of glutamate and increases the horizontal cell light response. In histidine, the A-wave response to various light intensities in the dark-adapted retina increased more than fifty percent, corresponding to the effect on horizontal cells. In the presence of background light, although histidine-treated rod light responses remained Weber-Fechner-like, their increment threshold was raised significantly. This indicates that endogenous zinc feedback serves to increase rod sensitivity in a light-adapted retina, despite a corresponding reduction of threshold sensitivity in the dark. We propose that the increase in A-wave amplitude is a result of the increased conductance at the synaptic terminal and that the A-wave can be used to monitor changes in rod transmitter release. Furthermore, endogenous zinc may also provide the benefit of reducing metabolic stress and the risk of glutamate toxicity in the dark.
Topics: Dark Adaptation; Electroretinography; Light; Photoreceptor Cells; Photoreceptor Cells, Vertebrate; Retina
PubMed: 33387934
DOI: 10.1016/j.visres.2020.12.005 -
Scientific Reports Oct 2019The keen visual systems of birds have been relatively well-studied. The foundations of avian vision rest on their cone and rod photoreceptors. Most birds use four cone...
The keen visual systems of birds have been relatively well-studied. The foundations of avian vision rest on their cone and rod photoreceptors. Most birds use four cone photoreceptor types for color vision, a fifth cone for achromatic tasks, and a rod for dim-light vision. The cones, along with their oil droplets, and rods are conserved across birds - with the exception of a few shifts in spectral sensitivity - despite taxonomic, behavioral and ecological differences. Here, however, we describe a novel photoreceptor organelle in a group of New World flycatchers (Empidonax spp.) in which the traditional oil droplet is replaced with a complex of electron-dense megamitochondria surrounded by hundreds of small, orange oil droplets. The photoreceptors with this organelle were unevenly distributed across the retina, being present in the central region (including in the fovea), but absent from the retinal periphery and the area temporalis of these insectivorous birds. Of the many bird species with their photoreceptors characterized, only the two flycatchers described here (E. virescens and E. minimus) possess this unusual retinal structure. We discuss the potential functional significance of this unique sub-cellular structure, which might provide an additional visual channel for these small predatory songbirds.
Topics: Animals; Photoreceptor Cells, Vertebrate; Phylogeny; Retina; Retinal Cone Photoreceptor Cells; Songbirds
PubMed: 31645645
DOI: 10.1038/s41598-019-51774-w -
Cell Reports Oct 2017Intrinsically photosensitive retinal ganglion cells of the M1 type encode environmental irradiance for functions that include circadian and pupillary regulation. Their...
Intrinsically photosensitive retinal ganglion cells of the M1 type encode environmental irradiance for functions that include circadian and pupillary regulation. Their distinct role, morphology, and molecular markers indicate that they are stereotyped circuit elements, but their physiological uniformity has not been investigated in a systematic fashion. We have profiled the biophysical parameters of mouse M1s and found that extreme variation is their hallmark. Most parameters span 1-3 log units, and the full range is evident in M1s that innervate brain regions serving divergent functions. Biophysical profiles differ among cells possessing similar morphology and between neighboring M1s recorded simultaneously. Variation in each parameter is largely independent of that in others, allowing for flexible individualization. Accordingly, a common stimulus drives heterogeneous spike outputs across cells. By contrast, a population of directionally selective retinal ganglion cells appeared physiologically uniform under similar conditions. Thus, M1s lack biophysical constancy and send diverse signals downstream.
Topics: Animals; Female; Male; Mice; Mice, Inbred C57BL; Photoreceptor Cells; Retinal Ganglion Cells; Rod Opsins; Vision, Ocular
PubMed: 29069587
DOI: 10.1016/j.celrep.2017.09.095 -
Proceedings of the National Academy of... Oct 2000Ribozyme-directed cleavage of mutant mRNAs appears to be a potentially effective therapeutic measure for dominantly inherited diseases. We previously demonstrated that...
Ribozyme-directed cleavage of mutant mRNAs appears to be a potentially effective therapeutic measure for dominantly inherited diseases. We previously demonstrated that two ribozymes targeted to the P23H mutation in rhodopsin slow photoreceptor degeneration in transgenic rats for up to 3 months of age when injected before significant degeneration at postnatal day (P) 15. We now have explored whether ribozyme rescue persists at older ages, and whether ribozymes are effective when injected later in the degeneration after significant photoreceptor cell loss. Recombinant adeno-associated virus (rAAV) vectors incorporating a proximal bovine rod opsin promoter were used to transfer either hairpin or hammerhead ribozyme genes to photoreceptors. For the study of long-term survival, rAAV was administered by subretinal injection at P15, and the rats were allowed to live up to 8 months of age. For the study of late-stage gene transfer, rAAV was administered at P30 or P45, when 40-45% of the photoreceptors already had degenerated. Eyes were examined functionally by the electroretinogram and structurally by morphometric analysis. When injected at P15, expression of either ribozyme markedly slowed the rate of photoreceptor degeneration for at least 8 months and resulted in significantly greater electroretinogram amplitudes at least up to P180. When injected at P30 or P45, virtually the same number of photoreceptors survived at P130 as when injected at P15. Ribozyme rescue appears to be a potentially effective, long-term therapy for autosomal dominant retinal degeneration and is highly effective even when the gene transfer is done after significant photoreceptor cell loss.
Topics: Animals; Animals, Genetically Modified; Cell Survival; Genetic Therapy; Photoreceptor Cells; RNA, Catalytic; Rats; Retinal Diseases
PubMed: 11005848
DOI: 10.1073/pnas.210319397 -
The Journal of Neuroscience : the... Mar 2006Synaptic depression produced by repetitive stimulation is likely to be particularly important in shaping responses of second-order retinal neurons at the tonically... (Comparative Study)
Comparative Study
Synaptic depression produced by repetitive stimulation is likely to be particularly important in shaping responses of second-order retinal neurons at the tonically active photoreceptor synapse. We analyzed the time course and mechanisms of synaptic depression at rod and cone synapses using paired-pulse protocols involving two complementary measurements of exocytosis: (1) paired whole-cell recordings of the postsynaptic current (PSC) in second-order retinal neurons and (2) capacitance measurements of vesicular membrane fusion in rods and cones. PSCs in ON bipolar, OFF bipolar, and horizontal cells evoked by stimulation of either rods or cones recovered from paired-pulse depression (PPD) at rates similar to the recovery of exocytotic capacitance changes in rods and cones. Correlation between presynaptic and postsynaptic measures of recovery from PPD suggests that 80-90% of the depression at these synapses is presynaptic in origin. Consistent with a predominantly presynaptic mechanism, inhibiting desensitization of postsynaptic glutamate receptors had little effect on PPD. The depression of exocytotic capacitance changes exceeded depression of the presynaptic calcium current, suggesting that it is primarily caused by a depletion of synaptic vesicles. In support of this idea, limiting Ca2+ influx by using weaker depolarizing stimuli promoted faster recovery from PPD. Although cones exhibit much faster exocytotic kinetics than rods, exocytotic capacitance changes recovered from PPD at similar rates in both cell types. Thus, depression of release is not likely to contribute to differences in the kinetics of transmission from rods and cones.
Topics: Animals; Benzothiadiazines; Dose-Response Relationship, Radiation; Electric Capacitance; Electric Stimulation; Exocytosis; Glutamates; In Vitro Techniques; Indoles; Neural Inhibition; Patch-Clamp Techniques; Photoreceptor Cells; Presynaptic Terminals; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Synapses; Time Factors; Urodela; Visual Pathways
PubMed: 16510733
DOI: 10.1523/JNEUROSCI.3667-05.2006 -
International Journal of Molecular... Oct 2019The retina is the light sensitive part of the eye and nervous tissue that have been used extensively to characterize the function of the central nervous system. The... (Review)
Review
The retina is the light sensitive part of the eye and nervous tissue that have been used extensively to characterize the function of the central nervous system. The retina has a central position both in fundamental biology and in the physiopathology of neurodegenerative diseases. We address the contribution of functional genomics to the understanding of retinal biology by reviewing key events in their historical perspective as an introduction to major findings that were obtained through the study of the retina using genomics, transcriptomics and proteomics. We illustrate our purpose by showing that most of the genes of interest for retinal development and those involved in inherited retinal degenerations have a restricted expression to the retina and most particularly to photoreceptors cells. We show that the exponential growth of data generated by functional genomics is a future challenge not only in terms of storage but also in terms of accessibility to the scientific community of retinal biologists in the future. Finally, we emphasize on novel perspectives that emerge from the development of redox-proteomics, the new frontier in retinal biology.
Topics: Animals; Genomics; Humans; Photoreceptor Cells; Proteome; Retinal Degeneration; Transcriptome
PubMed: 31590277
DOI: 10.3390/ijms20194922 -
Comptes Rendus Biologies Feb 2005Neuroprotection of photoreceptor cells in rod-cone dystrophies: from cell therapy to cell signalling. Neuroprotection of photoreceptor cells in rod-cone degenerations is... (Review)
Review
Neuroprotection of photoreceptor cells in rod-cone dystrophies: from cell therapy to cell signalling. Neuroprotection of photoreceptor cells in rod-cone degenerations is primarily targeted at preventing the loss of function. Strategies for protecting rod cells should therefore aim not only at structural preservation but also must be assessed using functional parameters (e.g., electroretinogram). Given the number of mutations leading to an impaired visual response of rods, the preservation of cones is a realistic approach since (1) numerous mutations do not affect proteins expressed by cones; (2) the secondary degeneration of cones is the main event leading to profound visual impairment; (3) even a small proportion of functional cones is sufficient for major visual functions. Our group has (1) established and confirmed the existence of non cell autonomous mechanisms promoting cone cell viability; (2) shown that rod cell protection or replacement provides a mean to extend the survival of cones; (3) demonstrated that rod-cone trophic interactions are mediated by diffusible proteins; (4) identified by expression cloning a protein mediating such interactions: RdCVF (Rod-derived Cone Viability Factor). These studies provide clues for broad neuroprotective therapies of rod-cone dystrophies.
Topics: Animals; Humans; Photoreceptor Cells, Vertebrate; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Signal Transduction; Vision, Ocular
PubMed: 15771002
DOI: 10.1016/j.crvi.2004.12.007