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PubMed2006

Retinal repair by transplantation of photoreceptor precursors.

Photoreceptor loss causes irreversible blindness in many retinal diseases. Repair of such damage by cell transplantation is one of the most feasible types of central nervous system repair; photoreceptor degeneration initially leaves the inner retinal circuitry intact and new photoreceptors need only make single, short synaptic connections to contribute to the retinotopic map. So far, brain- and retina-derived stem cells transplanted into adult retina have shown little evidence of being able to integrate into the outer nuclear layer and differentiate into new photoreceptors. Furthermore, there has been no demonstration that transplanted cells form functional synaptic connections with other neurons in the recipient retina or restore visual function. This might be because the mature mammalian retina lacks the ability to accept and incorporate stem cells or to promote photoreceptor differentiation. We hypothesized that committed progenitor or precursor cells at later ontogenetic stages might have a higher probability of success upon transplantation. Here we show that donor cells can integrate into the adult or degenerating retina if they are taken from the developing retina at a time coincident with the peak of rod genesis. These transplanted cells integrate, differentiate into rod photoreceptors, form synaptic connections and improve visual function. Furthermore, we use genetically tagged post-mitotic rod precursors expressing the transcription factor Nrl (ref. 6) (neural retina leucine zipper) to show that successfully integrated rod photoreceptors are derived only from immature post-mitotic rod precursors and not from proliferating progenitor or stem cells. These findings define the ontogenetic stage of donor cells for successful rod photoreceptor transplantation.

Animals↗
PubMed1987

Coupling of photoexcited rhodopsin to inositol phospholipid hydrolysis in fly photoreceptors.

Fly photoreceptor membranes were used to test the effect on defined biochemical reactions of light and of compounds causing photoreceptor excitation. Complementary electrophysiological studies examined whether putative second messengers excite the fly photoreceptor cells. This analysis revealed the following sequence of events: photoexcited rhodopsin activates a G protein by facilitating GTP binding. The G protein then activates a phospholipase C that generates inositol trisphosphate, which in turn acts as an internal messenger to bring about depolarization of the photoreceptor cell. Binding assays of GTP analogs and measurements of GTPase activity showed that there are 1.6 million copies of G protein per photoreceptor cell. The GTP binding component is a 41-kDa protein, and the light-activated GTPase is dependent on photoconversion of rhodopsin to metarhodopsin. Analysis of phospholipase C activity revealed that this enzyme is under stringent control of the G protein, that the major product formed is inositol trisphosphate, and that this product is rapidly hydrolyzed by a specific phosphomonoesterase. Introduction of inositol trisphosphate to the intact photoreceptor cell mimics the effect of light, and bisphosphoglycerate, which inhibits inositol trisphosphate hydrolysis, enhances the effects of inositol trisphosphate and of dim light. The interaction of photoexcited rhodopsin with a G protein is thus similar in both vertebrate and invertebrate photoreceptors. These G proteins, however, activate different photoreceptor enzymes: phospholipase C in invertebrates and cGMP phosphodiesterase in vertebrates.

Animals↗
PubMed1995

Transfer of graded potentials at the photoreceptor-interneuron synapse.

To characterize the transfer of graded potentials and the properties of the associated noise in the photoreceptor-interneuron synapse of the blowfly (Calliphora vicina) compound eye, we recorded voltage responses of photoreceptors (R1-6) and large monopolar cells (LMC) evoked by: (a) steps of light presented in the dark; (b) contrast steps; and (c) pseudorandomly modulated contrast stimuli at backgrounds covering 6 log intensity units. Additionally, we made recordings from photoreceptor axon terminals. Increased light adaptation gradually changed the synaptic signal transfer from low-pass to band-pass filtering. This was accompanied by decreased synaptic delay and increased contrast gain, but the overall synaptic gain and the intrinsic noise (i.e., transmission noise) were reduced. Based on these results, we describe a descriptive synaptic model, in which the kinetics of the tonic transmitter (histamine) release from the photoreceptor axon terminals change with mean photoreceptor depolarization. During signal transmission, tonic transmitter release is augmented by voltage-dependent contrast-enhancing mechanisms in the photoreceptor axons that produce fast transients from the rising phases of the photoreceptor responses and add these enhanced voltages to the original photoreceptor responses. The model can predict the experimental findings and it agrees with the recently proposed theory of maximizing sensory information.

Animals↗
PubMed2001

Light adaptation in Drosophila photoreceptors: I. Response dynamics and signaling efficiency at 25 degrees C.

Besides the physical limits imposed on photon absorption, the coprocessing of visual information by the phototransduction cascade and photoreceptor membrane determines the fidelity of photoreceptor signaling. We investigated the response dynamics and signaling efficiency of Drosophila photoreceptors to natural-like fluctuating light contrast stimulation and intracellular current injection when the cells were adapted over a 4-log unit light intensity range at 25 degrees C. This dual stimulation allowed us to characterize how an increase in the mean light intensity causes the phototransduction cascade and photoreceptor membrane to produce larger, faster and increasingly accurate voltage responses to a given contrast. Using signal and noise analysis, this appears to be associated with an increased summation of smaller and faster elementary responses (i.e., bumps), whose latency distribution stays relatively unchanged at different mean light intensity levels. As the phototransduction cascade increases, the size and speed of the signals (light current) at higher adapting backgrounds and, in conjunction with the photoreceptor membrane, reduces the light-induced voltage noise, and the photoreceptor signal-to-noise ratio improves and extends to a higher bandwidth. Because the voltage responses to light contrasts are much slower than those evoked by current injection, the photoreceptor membrane does not limit the speed of the phototransduction cascade, but it does filter the associated high frequency noise. The photoreceptor information capacity increases with light adaptation and starts to saturate at approximately 200 bits/s as the speed of the chemical reactions inside a fixed number of transduction units, possibly microvilli, is approaching its maximum.

Adaptation, Physiological↗
PubMed1997

Adenovirus-mediated gene transfer of ciliary neurotrophic factor can prevent photoreceptor degeneration in the retinal degeneration (rd) mouse.

Mutations in the beta-subunit of the cGMP phosphodiesterase gene (betaPDE) can cause photoreceptor degeneration leading to blindness in humans, dogs, and mice. Since intravitreal administration of trophic factors has been shown to reduce photoreceptor death in the Royal College of Surgeons rat and the light overexposure models of photoreceptor degeneration, we have tested the possibility of rescuing photoreceptors in the rd mouse using ciliary neurotrophic factor (CNTF). Following intravitreal injection of an adenoviral vector encoding a ngf/cntf fusion gene into one eye of rd/rd mice, many strong CNTF-immunoreactive profiles are detected in various cell types of the injected eyes. Semiquantitative analysis of the corresponding retinae reveals that the photoreceptor-containing layer (outer nuclear layer, or ONL) retains significantly more rows of photoreceptor nuclei than that of eyes treated with a control (LacZ) vector, or untreated, for at least 18 days after vector administration (the longest survival time analyzed). A smaller, but significant, protective effect was also seen 9 days after intravitreal injection of recombinant CNTF. Because apoptotic cell death has been shown to be the common terminal fate of photoreceptors in the rd mouse and many other animal models of retinitis pigmentosa, these results suggest the possibility that administration of neurotrophic factors may prove beneficial in reducing photoreceptor loss in multiple forms of retinitis pigmentosa.

Adenoviridae↗
PubMed1999

Diurnal rhythms of tryptophan hydroxylase activity in Xenopus laevis retina: opposing phases in photoreceptors and inner retinal neurons.

Tryptophan hydroxylase (TPH) is the first enzyme in the biosynthetic pathways of melatonin in photoreceptor cells and of serotonin in amacrine cells. To assess the regulation of TPH activity in photoreceptor cells, we pretreated retinas with kainic acid. The neurotoxin selectively killed inner retinal neurons while sparing photoreceptors. TPH activity in both control and kainate-treated retinas undergoes a day-night rhythm. The rhythms in both preparations fit sinusoidal functions. However, the rhythm in intact retinas peaks at midday while that in kainate-lesioned retinas does so at midnight. The daily rhythm of tryptophan hydroxylase activity in photoreceptors parallels that of melatonin release. Comparing the mean level of activity in rhythms of intact and lesioned retinas, we calculate that the TPH activity in photoreceptors represents 24% of the total activity. Therefore, the TPH activity measured in intact retinas reflects mainly the enzymatic activity in serotonergic neurons, masking that from photoreceptors. In contrast, the levels and diurnal variation of TPH mRNA did not differ in intact and kainate-lesioned retinas indicating that measurements of TPH mRNA content reflect primarily that in photoreceptor cells. Thus, TPH mRNA levels and enzyme activity are differentially regulated in amacrine neurons and photoreceptor cells. This differential regulation markedly impacts the patterns of daily rhythms observed in the intact retina.

Analysis of Variance↗
PubMed2003

Shaker K(+)-channels are predicted to reduce the metabolic cost of neural information in Drosophila photoreceptors.

Shaker K(+)-channels are one of several voltage-activated K(+)-channels expressed in Drosophila photoreceptors. We have shown recently that Shaker channels act as selective amplifiers, attenuating some signals while boosting others. Loss of these channels reduces the photoreceptor information capacity (bits s(-1)) and induces compensatory changes in photoreceptors enabling them to minimize the impact of this loss upon coding natural-like stimuli. Energy as well as coding is also an important consideration in understanding the role of ion channels in neural processing. Here, we use a simple circuit model that incorporates the major ion channels, pumps and exchangers of the photoreceptors to derive experimentally based estimates of the metabolic cost of neural information in wild-type (WT) and Shaker mutant photoreceptors. We show that in WT photoreceptors, which contain Shaker K(+)-channels, each bit of information costs approximately half the number of ATP molecules than each bit in Shaker photoreceptors, in which lack of the Shaker K(+)-channels is compensated by increased leak conductance. Additionally, using a Hodgkin-Huxley-type model coupled to the circuit model we show that the amount of leak present in both WT and Shaker photoreceptors is optimized to both maximize the available voltage range and minimize the metabolic cost.

Adenosine Triphosphate↗
PubMed1991

Ablation of Drosophila photoreceptor cells by conditional expression of a toxin gene.

We have used toxin-mediated ablation to study some aspects of visual system development in Drosophila melanogaster. To devise a method that permits the conditional expression of a cellular toxin, we introduced an amber mutation into the diphtheria toxin-A-chain gene. In transgenic animals, this toxin gene can be activated by providing the gene for an amber suppressor tRNA. By coupling this toxin gene to the photoreceptor cell-specific promoter of the chaoptic gene, photoreceptor cells could be specifically ablated during development. Photoreceptor cell-specific markers normally activated during pupal development failed to appear after midpupation. Photoreceptor cells were absent from the retinas of adult flies at eclosion. We have assessed the consequences of photoreceptor cell ablation for eye and optic lobe development. We suggest that the larval photoreceptor nerve is not essential, in the late larval stages, for retinula photoreceptor cell axons to achieve their proper projection pattern in the brain. Moreover, while retinula photoreceptor innervation is initially required for the development of normal optic ganglia, the ablation of these cells in midpupation has no discernible effect. This approach to cell-specific ablation should be generally applicable to the study of cellular functions in development and behavior.

Animals↗
PubMed2005

Excessive activation of cyclic nucleotide-gated channels contributes to neuronal degeneration of photoreceptors.

In different animal models, photoreceptor degeneration was correlated to an abnormal increase in cGMP concentration. The cGMP-induced photoreceptor toxicity was demonstrated by applying the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine on retinal explants. To assess the role of cGMP-gated channels in this cGMP toxicity, the Ca(2+) channel blockers verapamil and L- and D-diltiazem, which block cGMP-gated channels with different efficacies, were applied to in vitro animal models of photoreceptor degeneration. These models included: (i) adult rat retinal explants incubated with zaprinast, a more specific inhibitor of the rod phosphodiesterase than 3-isobutyl-1-methylxanthine and (ii) rd mouse retinal explants. Photoreceptor apoptosis was assessed by terminal dUTP nick end labelling and caspase 3 activation. Effects of the blockers on the synaptic rod Ca(2+) channels were measured by patch-clamp recording. In the zaprinast-induced photoreceptor degeneration model, both diltiazem isomers rescued photoreceptors whereas verapamil had no influence. Their neuroprotective efficacy was correlated to their inhibition of cGMP-gated channels (l-diltiazem>d-diltiazem>verapamil=0). In contrast, all three Ca(2+) channel blockers suppressed rod Ca(2+) channel currents similarly. This suppression of the currents by the diltiazem isomers was very weak (16.5%) at the neuroprotective concentration (10 microm). In rd retinal explants, both diltiazem isomers also slowed down rod degeneration in contrast to verapamil. L-diltiazem exhibited this effect at concentrations ranging from 1 to 20 microm. This study further supports the photoreceptor neuroprotection by diltiazem particularly in the rd mouse retina, whereas the absence of neuroprotection by verapamil further suggests the role of cGMP-gated channel activation in the induction of photoreceptor degeneration.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Opsin immunocytochemical characterization of different types of photoreceptors in the frog pineal organ.

The pineal organ of the frog, Rana esculenta and R. temporaria, was studied by opsin immunocytochemistry using two polyclonal antibovine rhodopsin and the monoclonal antichicken opsin antibodies OS-2 (detecting blue and green pigments) and COS-1 (detecting green and red pigments). Four types of photoreceptor cells were distinguished. The large outer segments of the numerous electron-dense photoreceptor cells ("large pineal rods") were immunoreactive with the rhodopsin and OS-2 antibodies, but reacted weakly with antibody COS-1. Some electron-dense photoreceptors with smaller outer segments ("small pineal rods") were found that were strongly OS-2-immunoreactive but moderately rhodopsin-positive. The long outer segments of the oil droplet containing photoreceptors ("large pineal cones") were only immunoreactive with the COS-1 antibodies. The small electron-lucent photoreceptors ("small pineal cones") were immunonegative with all the opsin antisera used. These results confirm the presence of the opsin of a (green-sensitive) rhodopsin in the "large rod" photoreceptors. A blue-sensitive pigment is supposed to be present in the "small rod" photoreceptors, and a red-sensitive one in the oil droplet-containing "large cones". The opsin-immunonegative "small cone" is discussed to contain a (UV-blue?) photopigment that differs essentially in its antigenic sites from the other pigments. The presence of four types of photoreceptors equipped with the opsins of apparently different photopigments strengthens the view that the frog pineal organ is capable of measuring different ranges of the light spectrum.

Animals↗
PubMed2006

Ionic currents underlying difference in light response between type A and type B photoreceptors.

In Hermissenda crassicornis, the memory of light associated with turbulence is stored as changes in intrinsic and synaptic currents in both type A and type B photoreceptors. These photoreceptor types exhibit qualitatively different responses to light and current injection, and these differences shape the spatiotemporal firing patterns that control behavior. Thus the objective of the study was to identify the mechanisms underlying these differences. The approach was to develop a type B model that reproduced characteristics of type B photoreceptors recorded in vitro, and then to create a type A model by modifying a select number of ionic currents. Comparison of type A models with characteristics of type A photoreceptors recorded in vitro revealed that type A and type B photoreceptors have five main differences, three that have been characterized experimentally and two that constitute hypotheses to be tested with experiments in the future. The three differences between type A and type B photoreceptors previously characterized include the inward rectifier current, the fast sodium current, and conductance of calcium-dependent and transient potassium channels. Two additional changes were required to produce a type A photoreceptor model. The very fast firing frequency observed during the first second after light onset required a faster time constant of activation of the delayed rectifier. The fast spike adaptation required a fast, noninactivating calcium-dependent potassium current. Because these differences between type A and type B photoreceptors have not been confirmed in comparative experiments, they constitute hypotheses to be tested with future experiments.

Action Potentials↗
PubMed1997

Reducing extracellular Cl- suppresses dihydropyridine-sensitive Ca2+ currents and synaptic transmission in amphibian photoreceptors.

A reduction in extracellular chloride suppresses light-evoked currents of second-order retinal neurons (bipolar and horizontal cells) by reducing release of glutamate from photoreceptors. The underlying mechanisms responsible for this action of reduced extracellular Cl- were studied with a combination of electrophysiological recordings from single neurons in a retinal slice preparation and image analyses of intracellular Ca2+ (Fura-2) and pH [2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester] in dissociated photoreceptors. The results show that reducing extracellular Cl- suppresses a dihydropyridine (DHP)-sensitive Ca2+ current (I(Ca)) in photoreceptors. It is proposed that suppression of I(Ca) results in suppression of photoreceptor neurotransmission. The suppressive effect of low Cl- on I(Ca) is not due to antagonism by the substituting anion nor is it mediated by changes in extracellular or intracellular pH. We conclude that normal extracellular levels of Cl- are important for maintenance of the voltage-gated Ca2+ channels that support neurotransmission from photoreceptors. Several ideas are presented about the mechanisms by which Cl- supports photoreceptor neurotransmission and the possibility that modulations of Cl- might play a physiological role in the regulation of Ca2+ channels in photoreceptors and, hence, photoreceptor function.

Ambystoma↗
PubMed2001

Variations in photoreceptor response dynamics across the fly retina.

Gradients in the spatial properties of retinal cells and their relation to image statistics are well documented. However, less is known of gradients in temporal properties, especially at the level of the photoreceptor for which no account exists. Using light flashes and white-noise-modulated light and current stimuli, we examined the spatial and temporal properties of a single class of photoreceptor (R1-6) within the compound eyes of male blowfly, Calliphora vicina. We find that there is a trend toward higher performance at the front of the eye, both in terms of spatiotemporal resolution and signal-to-noise ratio. The receptive fields of frontal photoreceptors are narrower than those of photoreceptors at the side and back of the eye and response speeds are 20% faster. The signal-to-noise ratio at high frequencies is also greatest at the front of the eye, allowing a 30-40% higher information rate. The power spectra of signals and noise indicate that this elevation of performance results both from shorter responses to individual photons and from a more reliable registration of photon arrival times. These distinctions are characteristic of adaptational changes that normally occur on increasing illumination. However, all photoreceptors were absorbing light at approximately the same mean photon rate during our recordings. We therefore suggest that frontal photoreceptors attain a higher state of light adaptation for a given photon rate. This difference may be achieved by a higher density of (Ca2+ permeable) light-gated channels. Consistent with this hypothesis, membrane-impedance measurements show that frontal photoreceptors have a higher specific conductance than other photoreceptors. This higher conductance provides a better temporal performance but is metabolically expensive. Across the eye, temporal resolution is not proportional to spatial (optical) resolution. Neither is it matched obviously to optic flow. Instead we examine the consequences of an improved temporal resolution in the frontal region for the tracking of small moving targets, a behavior exhibited by male flies. We conclude that the temporal properties of a given class of retinal neuron can vary within a single retina and that this variation may be functionally related to the behavioral requirements of the animal.

Animals↗
PubMed2003

Protective effect of docosahexaenoic acid on oxidative stress-induced apoptosis of retina photoreceptors.

PURPOSE: In a recent study, it was demonstrated that docosahexaenoic acid (DHA) promotes the survival of retinal photoreceptors in vitro, delaying apoptosis. However, lipid enrichment in DHA is known to contribute to retina vulnerability to oxidative stress. In this study, the effect of oxidative damage on rat retina neurons in vitro and whether DHA enhances or diminishes this damage were investigated. METHODS: Rat retina neurons in 3-day cultures, with or without DHA, were treated with the oxidant paraquat. After 24 hours, apoptosis, mitochondrial membrane integrity, and Bcl-2 and Bax expression were immunocytochemically determined. RESULTS: Paraquat induced apoptosis in amacrine and photoreceptor neurons, major neuronal types in the culture. Neuronal apoptosis was accompanied by mitochondrial membrane depolarization, an increase in the amount of photoreceptors expressing Bax, and a decrease in those expressing Bcl-2. Addition of DHA reduced photoreceptor apoptosis by almost half, simultaneously preserving their mitochondrial membrane integrity. DHA blocked the paraquat-induced increase in Bax expression and remarkably upregulated Bcl-2 expression. Glia-derived neurotrophic factor, a photoreceptor trophic factor, only slightly increased Bcl-2 expression and did not protect photoreceptors from oxidative damage. Similarly, other fatty acids tested did not prevent photoreceptor apoptosis. CONCLUSIONS: These results show that oxidative damage induces apoptosis in retinal neurons during their early development in culture and suggest that the loss of mitochondrial membrane integrity is crucial in the apoptotic death of these cells. DHA activates intracellular mechanisms that prevent this loss and by modulating the levels of pro- and antiapoptotic proteins of the Bcl-2 family selectively protect photoreceptors from oxidative stress.

Animals↗
PubMed2003

Basic fibroblast and epidermal growth factors stimulate survival in adult porcine photoreceptor cell cultures.

PURPOSE: To investigate the effects of basic fibroblast and epidermal growth factor (FGF2 and EGF, respectively) on the survival and phenotypic expression of photoreceptors isolated from adult mammalian retinas. METHODS: Primary cultures highly enriched in photoreceptors were prepared from adult domestic pig retinas and maintained in chemically defined medium. Cell culture composition was characterized through the use of specific antibody markers of retinal neurons, and neuronal survival was quantified through viability assays as a function of time in the presence or absence of different doses of FGF2 and EGF. Western blot analysis of phosphotyrosine residues was used to monitor activation of FGF2 and EGF signaling pathways. RESULTS: Reproducible survival of adult pig rod and cone photoreceptors was obtained for approximately 2 weeks in vitro, with the continued expression of rod opsin, recoverin, S-antigen, cone arrestin, and neuron-specific enolase. Purity of cultures was routinely more than 95% photoreceptors, with a rod-cone ratio of 2:3.1. Photoreceptor survival was stable for the initial week, decreasing slowly during the second, with rapid cell loss occurring thereafter. In the presence of FGF2 (20 ng/mL), the percentage of photoreceptor survival during the second week in culture was statistically significantly different, at least two times higher than in control experiments. Photoreceptor survival correlated directly with increasing concentrations of FGF2, and also of EGF. Combined treatment with FGF2 and EGF did not induce higher survival than either factor alone. There was no detectable selective loss of rods or cones in the experimental model. Phosphotyrosine immunoblots after stimulation of cultures with FGF2 and EGF revealed time-dependent appearance of multiple immunoreactive bands. CONCLUSIONS: The adult pig photoreceptor culture in the current study exhibits reproducible neuronal survival in vitro and represents a useful novel experimental system for the study of potential neuroprotective effects and signaling pathways of neurotrophic factors such as FGF2 and EGF in fully adult higher mammalian retina.

Animals↗
PubMed2004

Preventing retinal detachment-associated photoreceptor cell loss in Bax-deficient mice.

PURPOSE: To characterize photoreceptor cell apoptosis and cell loss in a mouse model of experimental retinal detachment (RD), and to use the technology of mouse genetics to study the molecular mechanisms underlying RD-associated photoreceptor degeneration. METHODS: Retinal detachments were created in adult wild-type and Bax-deficient mice by subretinal injection of 1.4% sodium hyaluronate. At 1, 3, 7, and 28 days after injection, animals were killed, eyes enucleated, and retinal sections studied by histochemistry, immunofluorescence labeling, and confocal microscopy. Rods and cones were labeled, and apoptotic cells were identified with terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). Photoreceptor cell apoptosis and cell loss were assessed quantitatively by counting both surviving and TUNEL-positive rods and cones. RESULTS: TUNEL-positive cells were found within the outer nuclear layer (ONL) of the detached portions of the retina. They were detected in the detached retina on day 1, peaked on day 3, and dropped precipitously after day 7 after RD. Photoreceptor cell loss of both rods and cones followed a similar time course after RD. Moreover, deletion of the proapoptotic gene Bax in a knockout mouse model abolished the RD-associated photoreceptor cell degeneration. CONCLUSIONS: Apoptosis is a major mechanism leading to photoreceptor cell death after RD. Blockage of the activity of the proapoptotic molecule Bax in a knockout mouse model prevents photoreceptor cell apoptosis and cell loss. These data suggest that the Bax-mediated apoptotic signaling pathway plays a critical role in RD-associated photoreceptor cell death.

Animals↗
PubMed2005

Cyclic AMP prevents retraction of axon terminals in photoreceptors prepared for transplantation: an in vitro study.

PURPOSE: Cell transplantation has emerged as a possible remedy for degeneration and injury in the central nervous system (CNS). In the retina, photoreceptor transplantation is a potential treatment for retinal degenerative disease. Graft survival has been well documented, but evidence of functional recovery is lacking. A major obstacle to recovery of vision is lack of synapse formation between grafted photoreceptors and host bipolar and horizontal cells. A prior study demonstrated that photoreceptors prepared for transplantation undergo rapid morphologic changes, including retraction of axon terminals toward their cell bodies, away from potential synaptic partners, a phenomenon that may interfere with graft-host synaptic interaction after transplantation. In this study, prevention of retraction of photoreceptor axon terminals was possible by pharmacological intervention. METHODS: Photoreceptor sheets, prepared by vibratome sectioning, and full-thickness retinas, harvested from adult porcine eyes, were maintained in culture and treated with either the cyclic adenosine monophosphate analogue 8-(4-chlorophenylthio)-cyclic 3',5'-adenosine monophosphate (CPT-cAMP), or forskolin, an adenylyl cyclase stimulant, for up to 48 hours. RESULTS: Both CPT-cAMP and forskolin treatments successfully blocked retraction of photoreceptor axon terminals. This effect was not due to cell toxicity and was reversed after removal of treatment, indicating its specificity. CONCLUSIONS: Pharmacological manipulation of photoreceptor axonal plasticity may improve graft-host synaptic interaction after subretinal photoreceptor cell transplantation.

Adenylyl Cyclases↗
PubMed2006

Machine learning approaches to supporting the identification of photoreceptor-enriched genes based on expression data.

BACKGROUND: Retinal photoreceptors are highly specialised cells, which detect light and are central to mammalian vision. Many retinal diseases occur as a result of inherited dysfunction of the rod and cone photoreceptor cells. Development and maintenance of photoreceptors requires appropriate regulation of the many genes specifically or highly expressed in these cells. Over the last decades, different experimental approaches have been developed to identify photoreceptor enriched genes. Recent progress in RNA analysis technology has generated large amounts of gene expression data relevant to retinal development. This paper assesses a machine learning methodology for supporting the identification of photoreceptor enriched genes based on expression data. RESULTS: Based on the analysis of publicly-available gene expression data from the developing mouse retina generated by serial analysis of gene expression (SAGE), this paper presents a predictive methodology comprising several in silico models for detecting key complex features and relationships encoded in the data, which may be useful to distinguish genes in terms of their functional roles. In order to understand temporal patterns of photoreceptor gene expression during retinal development, a two-way cluster analysis was firstly performed. By clustering SAGE libraries, a hierarchical tree reflecting relationships between developmental stages was obtained. By clustering SAGE tags, a more comprehensive expression profile for photoreceptor cells was revealed. To demonstrate the usefulness of machine learning-based models in predicting functional associations from the SAGE data, three supervised classification models were compared. The results indicated that a relatively simple instance-based model (KStar model) performed significantly better than relatively more complex algorithms, e.g. neural networks. To deal with the problem of functional class imbalance occurring in the dataset, two data re-sampling techniques were studied. A random over-sampling method supported the implementation of the most powerful prediction models. The KStar model was also able to achieve higher predictive sensitivities and specificities using random over-sampling techniques. CONCLUSION: The approaches assessed in this paper represent an efficient and relatively inexpensive in silico methodology for supporting large-scale analysis of photoreceptor gene expression by SAGE. They may be applied as complementary methodologies to support functional predictions before implementing more comprehensive, experimental prediction and validation methods. They may also be combined with other large-scale, data-driven methods to facilitate the inference of transcriptional regulatory networks in the developing retina. Furthermore, the methodology assessed may be applied to other data domains.

Animals↗