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PubMed2004

N-methyl-D-aspartate induces phosphorylation of cAMP response element (CRE)-binding protein and increases DNA-binding activity of CRE in rat retina.

The aim of this study was to investigate whether an excitotoxic concentration of N-methyl-D-aspartate (NMDA) increases the expression of the phosphorylated cAMP response element-binding protein (p-CREB) and the DNA-binding activity of the cAMP response element (CRE) in rat retina. Intravitreal injection of NMDA was performed in adult male Wistar rats. p-CREB protein levels in the retina were examined by Western blot analysis. DNA-binding activity of CRE in the retina was evaluated by an electrophoretic mobility gel shift assay (EMSA). We confirmed that NMDA induced the reduction of ganglion cells and the inner plexiform layer of the retina. Western blot analysis showed increases in the expression of p-CREB in the retina 12 and 24 h after intravitreal NMDA injection and dimer formation of CREB in the nuclear fraction at 24 h. Increases of DNA-binding activity were observed in the retina 24 h after NMDA injection by EMSA. Our results suggest that phosphorylation of CREB may involved in NMDA-induced excitotoxicity in rat retina. Phosphorylated CREB seems to be the active form and the one that is transcribed.

Animals↗
PubMed1991

NADPH-diaphorase positive neurons in the retina of Bufo marinus: selective staining of bipolar and amacrine cells.

Unfixed retinal tissues of adult Bufo marinus were reacted for NADPH-diaphorase histochemistry that resulted in selective staining of populations of bipolar and amacrine cells. The number of stained bipolar cells in the retina was estimated to be 233,600 +/- 38,900 (mean +/- S.D.). These cells were non-uniformly distributed across the retina with the highest density of 4,308 cells/mm2 along the visual streak decreasing to lowest density of 1,378 cells/mm2 at the dorsal and ventral poles of the retina. The stained bipolar cells represented a morphologically uniform population. The number of labelled amacrine cells in the retina amounted to 3,116 +/- 405 including 251 cells that were displaced into the ganglion cell layer. Labelled amacrine cells were also unevenly distributed; with no stained cells in the retinal centre from where the density increased steadily to 72 cells mm2 in the retinal periphery. NADPH-diaphorase positive amacrine cells were classified on the basis of their dendritic arborization pattern into three morphological types: 1) narrow-field cells both at the periphery and the centre of the retina; 2) wide-field amacrine cells, and 3) amacrines with eccentric medium-sized dendritic field. The results of this study provide evidence for the presence of NADPH-diaphorase containing neurons in the anuran retina. Furthermore, this is the first report on the selective staining of bipolar cells for NADPH-diaphorase in the vertebrate retina.

Animals↗
PubMed2003

Expression of membrane-bound and soluble guanylyl cyclase mRNAs in embryonic and adult retina of the medaka fish Oryzias latipes.

Localization of mRNAs for four membrane-bound guanylyl cyclases (membrane GCs; OlGC3, OlGC4, OlGC5, and OlGC-R2), three soluble guanylyl cyclase subunits (soluble GC; OlGCS-alpha(1), OlGCS-alpha(2), and OlGCS-beta(1)), neuronal nitric oxide synthase (nNOS), and cGMP-dependent protein kinase I (cGK I) was examined in the embryonic and adult retinas of the medaka fish Oryzias latipes by in situ hybridization. All of the membrane GC mRNAs were detected in the photoreceptor cells of the adult and embryonic retinas, but in different parts; the OlGC3 and OlGC5 mRNAs were expressed in the proximal part and the OlGC4 and OlGC-R2 mRNAs were expressed in the outer nuclear layer. The mRNA for nNOS was expressed in a scattered fashion on the inner side of the inner nuclear layer in the adult and embryonic retinas. The mRNAs (OlGCS-alpha(2) and OlGCS- beta(1)) of two soluble GC subunits (alpha(2) and beta(1)) were expressed mainly in the inner nuclear layer and the ganglion cell layer of the embryonic retina while the mRNAs of the soluble GC alpha(1) subunit and cGK I were not detected in either the adult or embryonic retina. These results suggest that NO itself and/or the cGMP generated by soluble GC (alpha(2)/beta(1) heterodimer) play a novel role in the neuronal signaling and neuronal development in the medaka fish embryonic retina in addition to the role played by phototransduction through membrane GCs in the adult and embryonic retinas.

Aging↗
PubMed1984

Ascorbate and glutathione levels in the developing normal and dystrophic rat retina: effect of intense light exposure.

Ascorbic acid and glutathione were measured in retinas excised from normal rats reared in a cyclic light or dark environment and in dystrophic rats from the dark environment. Similar measurements were made on retinas from age matched rats exposed to intense visible light for periods of up to 24 hours. In other rats, ascorbic acid was given for various periods before exposure to intense light and the degree of photoreceptor cell death determined subsequently by rhodopsin measurements. In non-intense light treated rats ascorbate and glutathione were 12.1 nmol/retina at 20 days of age and 13.3 - 15.9 nmol/retina in 60 day old animals. In dystrophic rat retinas glutathione was 4-8% higher and ascorbate 10-20% higher than in normal dark reared rats. Although the levels of ascorbate and glutathione per retina increased during development, the molar ratios of the antioxidant materials to rhodopsin decreased by 36% and 60% in normal and dystrophic rats respectively. The levels of glutathione in young cyclic light or dark reared normals were unaffected by intense light exposure of either short (2-4 hrs) or long (24 hrs) duration. However, in both 20 and 40 day old dystrophic rats, intense light exposure resulted in a significant increase in retinal glutathione. In contrast to glutathione, retinal ascorbate decreased in normal rats exposed to intense light for 24 hrs, in an age and prior light environment dependent fashion. At ages greater than 20 days, normal rats exposed to light had significantly lower retinal ascorbate levels than their non-light exposed counterparts. The levels of ascorbate in 21-40 and 41-60 day old dark reared rat retinas were also significantly lower than in comparable intense light treated-cyclic light reared rats. In the youngest dystrophic rats whole eye ascorbate (retina, RPE, choroid and sclera) was 20-30% lower than in non-light treated rats, but in older mutant rats (41-60 day) light had no effect on the level of ascorbate in the retina. As determined by the level of rhodopsin remaining in the eye two weeks after 24 hrs light exposure, cyclic light reared rats lost 50-55% of their visual cells. However, cyclic light rats supplemented with ascorbic acid before intense light exposure lost only 30-35% of their visual cells.

Age Factors↗
PubMed1984

Purification and characterization of glutathione S-transferases in human retina.

Human retina has two forms of glutathione (GSH) S-transferases. These forms having pI 4.5 and greater than 10 have been purified and their kinetic, structural and immunological characteristics are described. Both the enzymes of human retina do not express glutathione peroxidase II activity. The anionic enzyme (pI 4.5) of retina cross reacts with the antibodies raised against the anionic GSH S-transferases of human lung and placenta but does not cross react with the antibodies raised against the cationic enzymes of human liver. On the other hand, the cationic enzyme (pI greater than 10) of human retina cross reacts with the antibodies raised against the cationic GSH S-transferases of human liver but not with antibodies raised against the anionic enzymes of lung and placenta. Differences in the kinetic characteristics of the two forms of human retinal GSH S-transferases are also indicated. Results of these studies suggest that the anionic enzyme of retina may be similar to the anionic enzymes of lung and placenta. However, the cationic form appears to be different from all other GSH S-transferases of human tissues characterized so far. Human retina has selenium dependent glutathione peroxidase I and in this respect is different from bovine retina which has no glutathione peroxidase I as demonstrated in earlier studies.

Cross Reactions↗
PubMed1992

Immunohistochemical localization of basic fibroblast growth factor in mature and developing retinas of normal and RCS rats.

Basic fibroblast growth factor (bFGF) delays photoreceptor degeneration when injected intraocularly in Royal College of Surgeons (RCS) rats with inherited retinal dystrophy. In the present study, we have determined the localization of endogenous bFGF in retinas of normal and RCS rats during the normal developmental period (postnatal days 0-20) and the period of photoreceptor degeneration in RCS rats (days 20-90). bFGF was localized immunohistochemically by indirect immunoperoxidase using two different polyclonal antibodies and one monoclonal antibody against bFGF. bFGF was present in retinas as early as birth, and remained through adult age. Controls using either PBS, non-immune IgG or antibody preabsorbed with bFGF peptide were devoid of label. In normal rats between the ages of birth and postnatal day (P) 4, bFGF was found in developing ganglion cells, superficial blood vessels, some of the innermost cells in the neuroblastic layer, developing horizontal cells, and retinal pigment epithelial (RPE) cells. Between P0 and P4, the intensity of staining increased significantly in horizontal cells. From P6-P10, some cells in the inner nuclear layer remained positive, but horizontal cell staining became less intense in the central retina. The superficial vessels, ganglion cells and RPE cells also remained positive for bFGF. At P20-25, when the retina was essentially mature, bFGF was found in RPE cells, most cells of the ganglion cell layer, and many cells of the inner nuclear layer, but horizontal cells and blood vessels showed a lower concentration of bFGF than they did at younger ages. At P45 and older, blood vessels no longer showed bFGF immunoreactivity. The staining pattern in RCS rats was indistinguishable from that for normal rats at all ages examined. These results show that bFGF is present in the developing and adult rat retina in some neural cells, in addition to vessels and RPE cells. The transient elevated expression of bFGF immunoreactivity in developing horizontal cells and blood vessels suggests a possible role for this growth factor in retinal development. In addition, if RCS retinas possess any difference in bFGF localization or concentration compared to normal retinas, it must be too small to detect by immunohistochemical means, or at least with the reagents used.

Animals↗
PubMed1993

Muller cell expression of glial fibrillary acidic protein (GFAP) in RPE-cell transplanted retinas of RCS dystrophic rats.

In Royal College of Surgeons (RCS) rats with inherited retinal dystrophy, photoreceptor cell degeneration is accompanied by Muller cell changes, in particular, increased expression of the intermediate filament protein, glial fibrillary acidic protein (GFAP). In this study, we examined the expression of GFAP in retinas of 4 month-old RCS dystrophic rats either transplanted with normal retinal pigment epithelial (RPE) cells or injected with vehicle (sham control). The sham-injected and non-treated retinas showed increased expression of GFAP in Muller cells with advancing age. GFAP-immunostained Muller processes were observed in the region of the subretinal space of these RCS retinas beginning by 4 months. However, in the retinas of RCS rats transplanted with normal RPE cells, GFAP expression by Muller cells was significantly reduced. Specifically, under the transplanted RPE cells, GFAP-immunolabeled Muller radial processes were not observed and GFAP immunostaining was not present in the subretinal space at any time period examined. Immunoblot analysis of the superior hemisphere of RPE-cell transplanted retinas of 4 month-old RCS dystrophic rats showed less GFAP immunostaining than sham-injected and the inferior hemisphere of retinas of age-matched RCS rats. This study showed that in normal RPE-cell transplanted retinas of RCS rats, in addition to rescued photoreceptor cells, there was an accompanying stabilization of Muller cells as demonstrated by a reduction in the expression of GFAP.

Animals↗
PubMed1994

The combined effects of diabetes and ionising radiation on the rat retina: an ultrastructural study.

The combined effect of STZ-diabetes and ionising radiation on the rat retina was investigated. Wistar rats, which had been diabetic for 6 months, were irradiated with a single dose of x-rays (1500 cGy) and the ultrastructural effects evaluated at 4-10 mths post-irradiation. At 4 months post-irradiation, the outer nuclear layer of the retina was greatly reduced in thickness and the photoreceptor outer segments were disorganised and reduced in length. In addition, the nerve fibre layer contained many cytoid bodies and there were many redundant basement membrane tubes throughout the inner retina. By 6 months post-irradiation, the photoreceptor cells were virtually absent, bringing the external limiting membrane into close apposition to the RPE. Throughout large areas of the outer retina, RPE cells were hypertrophic and some had proliferated into the inner retina. In many regions, proliferating retinal capillaries were observed within the RPE layer, and at 8 months post-irradiation, some vessels extended into the inner retina accompanied by RPE cells. At 10 months post-irradiation, the RPE was atrophic and degenerative with retinal glial cells coming into contact with Bruch's membrane. In some areas, the glia which had breached Bruch's membrane had invaded the underlying choroid. Where glial cells contacted the choriocapillaries, the vessels assumed the appearance of retinal vessels with plump endothelia and no fenestrations. This study has described a progressive inner retinal ischemia, with cytoid bodies, capillary non-perfusion and general atrophy of the inner retina intensifying markedly with increasing post-irradiation time.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Calpain activity in the retinas of normal and RCS rats.

Calpains are calcium-activated proteinases which have been implicated in tissue differentiation and degeneration. The aims of the present study were: (1) to determine the relationship between postnatal age and calpain activity in the rat retina; (2) to test if calpain activity was aberrant in the RCS retina at different postnatal ages. Calpain activity was measured by a standard in vitro assay in fractions of retinas of rats, ranging in postnatal age of 2 to 42 days. Most retinal calpain activity was in the cytosolic fraction. Specific calpain activity declined with age. In the Long Evans rat, it was 8-fold higher on postnatal day 2 than on postnatal day 42. Comparison between RCS rats and their congenic controls showed that calpain activity was lower in the retinas of neonatal RCS rats. Specific calpain activity in RCS rat retinas was 46% lower on postnatal day 2 and 22% lower on postnatal day 3. It is concluded that during postnatal development of the retina, marked changes occurred in calpain activity. In addition, calpain activity is abnormal in the retina of the neonatal RCS rat--well before the onset of any morphological deterioration and preceding any other previously detected abnormality. Aberrant calpain activity appears to be a manifestation of very early events in processes that lead to retinal degeneration in the RCS rat.

Aging↗
PubMed1999

N-methyl-D-aspartate (NMDA)--induced apoptosis in rat retina.

PURPOSE: The involvement of apoptosis in N-methyl-D-aspartate (NMDA)-induced excitotoxicity in adult rat retinas was examined. METHODS: Excitotoxic loss of inner retinal elements was induced by intravitreal injections of various concentrations of neutralized NMDA in adult albino Lewis rats. Tissue responses were quantified by measuring the inner retinal thickness (IRT) in plastic sections of the retinas and cell counts in the retinal ganglion cell layer in flatmount preparations of the whole retinas. Internucleosomal DNA fragmentation, a hallmark of apoptosis, was assayed with agarose DNA gel electrophoresis. The in situ TdT-mediated biotin-dUTP nick end labeling (TUNEL) method was used to locate nicked DNA in paraffin sections of the retinas. Ultrastructural changes of the degenerating cells were examined by electron microscopy. The efficacy of Ac-Tyr-Val-Ala-Asp-CMK (YVAD-CMK), a peptidyl caspase inhibitor, and 3-aminobenzamide (ABA), an inhibitor of poly(ADP-ribose) polymerase (PARP), in ameliorating the loss of inner retinal elements was evaluated using morphometry to examine the apoptotic pathways. RESULTS: Intravitreal injection of NMDA induced a dose-dependent loss of inner retinal elements as evidenced by the measurements of IRT and RGCCs. There were time- and dose-related appearances of internucleosomal fragmentation of retinal DNA and a time-related appearance of TUNEL-positive nuclei in the inner retinas after intravitreal NMDA injection. Ultrastructural features consistent with classic apoptotic changes were noted in degenerating cells in the retinal ganglion cell layer and the inner nuclear layer. Control retinas given vehicle, N-methyl-L-aspartate (the L-isomer of NMDA), or NMDA plus MK-801, a specific antagonist, did not show these changes. Simultaneous administration of NMDA and YVAD-CMK or ABA abolished or attenuated the loss of RGCCs in the posterior retinas. CONCLUSIONS: NMDA-induced excitotoxicity involved apoptosis and caspases and PARP may play important roles in the pathways.

Amino Acid Chloromethyl Ketones↗
PubMed1999

Cell-specific expression of tubby gene family members (tub, Tulp1,2, and 3) in the retina.

PURPOSE: The family of tubby-like proteins (TULPs), consisting of four family members, are all expressed in-the retina at varying levels. Mutations within two members, tub and TULP1, are known to lead to retinal degeneration in mouse and humans, respectively, suggesting the functional importance of this family of proteins in the retina. Despite a high degree of conservation in the carboxy-terminal region (e.g., putative functional domain of the genes) among family members, they are unable to compensate for one another. The purpose of this study was to provide a rationale for this lack of compensation by investigating the spatial distribution of tubby gene family members in the retina and to investigate the mechanism of photoreceptor cell death in tubby mice. METHODS: In situ hybridization using riboprobes specific for each tubby gene family member and immunohistochemistry for TUB and TULP1 were performed to determine their expression patterns in the retina of tubby and wild-type control mice. The terminal dUTP nick-end labeling (TUNEL) assay was performed to detect apoptotic cells in the retina of tubby and wild-type control mice. RESULTS: tub mRNA was found to be expressed throughout the retina, with highest expression in the ganglion cell layer (GCL) and photoreceptor cells. In contrast, Tulp1 expression was observed only in photoreceptor cells and Tulp3 mRNA was expressed at a moderate level only in the inner nuclear layer (INL) and GCL. The results of the immunohistochemical analysis paralleled those observed in the in situ studies. TUB immunoreactivity was most highly concentrated in the GCL, in the inner and outermost regions of the INL, in the outer plexiform layer (OPL), and in the inner segments of photoreceptor cells. Similarly, TULP1 immunoreactivity was observed in the OPL and inner segments of the photoreceptor cells. No differences in expression at the mRNA or protein level were observed for any of the molecules tested in tubby or wild-type mice. TUNEL-positive cells were detected in the ONL of tubby mice, whereas very few were seen in the same layer of age-matched control mice. CONCLUSIONS: Although all tubby gene family members are expressed in the retina, they each have different cell-specific expression patterns, which may account in part for their inability to compensate for the loss of one family member. The photoreceptor cell death in tubby mice occurs through an apoptotic mechanism, which is known to be the common final outcome of other forms of retinal degeneration.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Dose dependency of canthaxanthin crystals in monkey retina and spatial distribution of its metabolites.

PURPOSE: To establish the threshold level of canthaxanthin crystals in the retina of cynomolgus monkeys. To correlate the spatial distribution of all-trans canthaxanthin and its metabolites with the grade of crystals. METHODS: Monkeys were orally administered 0, 0.2, 0.6, 1.8, 5.4, 16.2, and 48.6 mg/kg body wt canthaxanthin daily for 2.5 to 3 years. A second group of monkeys were administered 200 and 500 mg/kg body wt/d for 5 years. Ophthalmoscopy, electroretinography (ERG), retina and carotenoid analysis were performed as previously reported. RESULTS: Crystals in the retina periphery were observed by ophthalmoscopy preterminally only in the extreme high doses of 200 to 500 mg/kg body wt/d. There were no adverse effects on visual functions as measured by ERG. Crystals in the peripheral retina, and/or in the macula, were detected microscopically in all canthaxanthin treated groups except at the lowest dose of 0.2 mg/kg body wt/d. The grade of crystals increased up to a dose of 16.2 mg/kg body wt/d. Dose-dependent increases in canthaxanthin content also were noted in the retina, the liver, and in plasma. All-trans canthaxanthin was the major compound in the peripheral and paracentral retina of very highly dosed animals, where its concentration correlated largely with the grade of inclusions. In the macula, 4'-OH-echinenone was the dominant canthaxanthin metabolite. CONCLUSIONS: The grade of crystals in monkey retinas was dose dependent with a threshold level at 0.6 mg canthaxanthin/kg body wt/d. It correlated in the retinal periphery with the concentrations of all-trans-canthaxanthin and in the macula with its metabolites.

Administration, Oral↗
PubMed2000

Spatiotemporal expression patterns of 6B4 proteoglycan/phosphacan in the developing rat retina.

PURPOSE: To investigate expression of 6B4 proteoglycan/phosphacan, the major constituent of chondroitin sulfate proteoglycan and a possible modulator of neural network formation in the developing central nervous system, in developing rat retina. METHODS: Changes in expression and localization of 6B4 proteoglycan in developing rat retina were investigated by reverse transcription-initiated polymerase chain reaction (RT-PCR), immunohistochemistry, and immunoblot analysis. RESULTS: Semiquantitative RT-PCR revealed that mRNA expression of 6B4 proteoglycan in retinas peaked at postnatal day 14 (P14) and then decreased at P42. Immunohistochemical analyses using MAb 6B4, a monoclonal antibody against 6B4 proteoglycan, revealed faint immunoreactivity in the inner aspects of the retina at embryonal day 16 (E16). At birth, weak immunoreactivity was present in the nerve fiber layer (NFL) and inner plexiform layer (IPL). At P7 and P14, the NFL, IPL, and outer plexiform layer (OPL) stained intensely, but the ganglion cell layer (GCL) remained unstained. Between P21 and P42, immunoreactivity in the NFL and IPL weakened slightly. Immunoblot analyses showed a MAb 6B4 immunopositive band in the retinal soluble fraction treated with chondroitinase ABC. The amount of the immunopositive band increased rapidly as retinal development proceeded. Surprisingly, a significant amount of the immunopositive band was present in the retina even before digestion with chondroitinase ABC, indicating that at least part of 6B4 proteoglycan in rat retina exists in a non-proteoglycan form. CONCLUSIONS: The existence of 6B4 proteoglycan/phosphacan was thus demonstrated in rat retina, although some biochemical parameters were different from those of the 6B4 proteoglycan seen in brain.

Animals↗
PubMed2000

Osteonectin/SPARC secreted by RPE and localized to the outer plexiform layer of the monkey retina.

PURPOSE: Osteonectin/SPARC is a secreted protein that has been implicated in ocular disease. Deletion of osteonectin/SPARC causes age-onset cataract in mice and the cataractous human lens has increased expression of osteonectin/SPARC. In this study, the expression and localization of osteonectin/SPARC in the monkey retina were determined as was secretion by cultured human retinal pigment epithelial (RPE) cells. METHODS: Adult Rhesus monkey eyes (Macaca mulatta) were dissected, and 5-mm macula and peripheral retina punches were obtained. Supernatants were collected from cultured human RPE cells. Subcellular fractionation of whole monkey retina was also performed. Osteonectin/SPARC expression and/or secretion was monitored by Northern and Western blot analyses, and localization was determined by immunocytochemistry. RESULTS: Outside of the retina osteonectin/SPARC mRNA is broadly expressed in many human tissues. Northern blot analysis shows that in the retina osteonectin/SPARC is expressed almost exclusively by the macular RPE/choroid. Western blot analysis revealed osteonectin/SPARC in both the macula and the peripheral neural retina but only in trace amounts in the RPE/choroid. In subcellular fractions of the whole retina, osteonectin/SPARC was detected, mainly in the soluble fraction but also in the membrane and nuclear fractions. Immunohistochemical analysis localized osteonectin/SPARC specifically to the outer plexiform layer. Western blot analysis of conditioned medium from human RPE cells cultured on porous substrates indicated that osteonectin/SPARC is secreted in large amounts from both the apical and basal sides of the RPE. CONCLUSIONS: Collectively these data provide evidence that osteonectin/SPARC is synthesized in the macular RPE, secreted, and subsequently transported to the outer plexiform layer. The expression pattern of osteonectin/SPARC in the subcellular retinal fractions is consistent with a soluble protein that is transported and internalized.

Animals↗
PubMed2000

A novel resource for the study of genes expressed in the adult human retina.

PURPOSE: To reconstruct the transcriptional profile of the human adult retina and the genomic map of the genes expressed in this tissue. METHODS: Original software was used for the retrieval and analysis of records from UniGene (http://www.ncbi.nlm.nih. gov/UniGene/) pertaining to selected cDNA libraries from adult human retina. RESULTS: The 4974 genes reported so far to be expressed in retina were included in a catalog available on the Internet. For each entry, an estimation of the level of expression of the corresponding gene in the retina was provided. A high-resolution genomic map of the human retina was built up by inclusion of 3152 genes showing a precise and unique map assignment. The correspondence was established between 53 gene-orphan retinal diseases and clusters of genes expressed in the retina. CONCLUSIONS: The in silico reconstruction of the transcriptional profile of the adult human retina provides preliminary information on the pattern of genomic expression in this tissue. The chromosomal location of many retinal genes, combined with their expression data, should speed up the identification of genes involved in retinal diseases.

Adult↗
PubMed2001

Abnormal centrifugal axons in streptozotocin-diabetic rat retinas.

PURPOSE: To characterize the effects of diabetes on the expression of histidine decarboxylase mRNA and on the morphology of the histaminergic centrifugal axons in the rat retina. METHODS: Rats were made diabetic by streptozotocin. After 3 months, retinal histidine decarboxylase expression was analyzed by in situ hybridization in radial sections. Flatmount retinas from a second group of rats were labeled with an antiserum to histamine or an antibody to phosphorylated neurofilament protein. RESULTS: Histidine decarboxylase mRNA was expressed in cells in the inner and outer nuclear layers of diabetic retinas, but not in normal retinas. However, immunoreactive (IR) histamine was not localized to perikarya in either the normal or the diabetic retinas. Instead, a population of centrifugal axons was labeled. These axons emerged from the optic disc and had varicose terminal branches in the inner plexiform layer (IPL) of the peripheral retina. Some branches ended on large retinal blood vessels and others in dense clusters in the IPL. In rats with streptozotocin-induced diabetes, the centrifugal axon terminals developed many large swellings that contained neurofilament immunoreactivity; these swellings were rare in normal retinas. CONCLUSIONS: Diabetes perturbs the retinal histaminergic system, causing increases in histidine decarboxylase mRNA expression in neurons or glia and abnormal focal swellings on the centrifugal axons.

Animals↗
PubMed2001

Atrophy of Müller glia and photoreceptor cells in chick retina misexpressing cNSCL2.

PURPOSE: To investigate whether and how the basic helix-loop-helix (bHLH) gene cNSCL2 is involved in retinal development. METHODS: cNSCL2, the chick homologue of human NSCL2, was isolated and sequenced. In situ hybridization was used to examine its spatial and temporal expression pattern in the retina. Replication-competent retrovirus RCAS was used to drive cNSCL2 misexpression in the developing chick retina, and the effect of the misexpression was analyzed. RESULTS: Expression of cNSCL2 in the retina was restricted. Its mRNA was detected in amacrine and horizontal cells, but not in photoreceptor, bipolar, or ganglion cells. Retroviral-driven misexpression of cNSCL2 in the developing chick retina resulted in missing photoreceptor cells and gross deficits in the outer nuclear layer (ONL). These deficits were probably not because of decreased photoreceptor production, in that the ONL appeared normal in early developmental stages. TUNEL+ cells were detected in the ONL, indicating that photoreceptor cells underwent apoptosis in retinas misexpressing cNSCL2. Müller glial cells were far fewer in the experimental retina than in the control, indicating that cNSCL2 also caused Müller glia atrophy. The onset of Müller glia disappearance preceded that of photoreceptor degeneration. CONCLUSIONS: Expression of cNSCL2 in the chick retina was restricted to amacrine and horizontal cells. Misexpression of cNSCL2 caused severe retinal degeneration, and photoreceptor cells and Müller glia were particularly affected.

Animals↗
PubMed2002

Functional magnetic resonance imaging of the retina.

PURPOSE: This study explored the feasibility of mapping the retina's responses to visual stimuli noninvasively, by using functional magnetic resonance imaging (fMRI). METHODS: fMRI was performed on a 9.4-Tesla scanner to map activity-evoked signal changes of the retina-choroid complex associated with visual stimulation in anesthetized cats (n = 6). Three to 12 1-mm slices were acquired in a single shot using inversion-recovery, echo-planar imaging with a nominal in-plane resolution of 468 x 468 microm(2). Visual stimuli were presented to the full visual field and to the upper and lower visual fields. The stimuli were drifting or stationary gratings, which were compared with the dark condition. Activation maps were computed using cross-correlation analysis and overlaid on anatomic images. Multislice activation maps were reconstructed and flattened onto a two-dimensional surface. RESULTS: fMRI activation maps showed robust increased activity in the retina-choroid complex after visual stimulation. The average stimulus-evoked fMRI signal increase associated with drifting-grating stimulus was 1.7% +/- 0.5% (P < 10(-4), n = 6) compared with dark. Multislice functional images of the retina flattened onto a two-dimensional surface showed relatively uniform activation. No statistically significant activation was observed in and around the optic nerve head. Hemifield stimulation studies demonstrated that stimuli presented to the upper half of the visual field activated the lower part of the retina, and stimuli presented to the lower half of the visual field activated the upper part of the retina, as expected. Signal changes evoked by the stationary gratings compared with the dark basal condition were positive but were approximately half that evoked by the drifting gratings (1.0% +/- 0.1% versus 2.1% +/- 0.3%, P < 10(-4)). CONCLUSIONS: To the best of our knowledge, this is the first fMRI study of the retina, demonstrating its feasibility in imaging retinal function dynamically in a noninvasive manner and at relatively high spatial resolution.

Animals↗