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PubMed2004

Quantification of the cytoplasmic spaces of living cells with EGFP reveals arrestin-EGFP to be in disequilibrium in dark adapted rod photoreceptors.

The hypothesis is tested that enhanced green fluorescent protein (EGFP) can be used to quantify the aqueous spaces of living cells, using as a model transgenic Xenopus rods. Consistent with the hypothesis, regions of rods having structures that exclude EGFP, such as the mitochondrial-rich ellipsoid and the outer segments, have highly reduced EGFP fluorescence. Over a 300-fold range of expression the average EGFP concentration in the outer segment was approximately half that in the most intensely fluorescent regions of the inner segment, in quantitative agreement with prior X-ray diffraction estimates of outer segment cytoplasmic volume. In contrast, the fluorescence of soluble arrestin-EGFP fusion protein in the dark adapted rod outer segment was approximately threefold lower than predicted by the EGFP distribution, establishing that the fusion protein is not equilibrated with the cytoplasm. Arrestin-EGFP mass was conserved during a large-scale, light-driven redistribution in which approximately 40% of the protein in the inner segment moved to the outer segment in less than 30 minutes.

Animals↗
PubMed1993

Expression of recoverin mRNA in the human retina: localization by in situ hybridization.

The localization of mRNA encoding recoverin in the human retina was examined by in situ hybridization. The riboprobe utilized in this study was transcribed from a cDNA clone containing the complete coding region of human recoverin. The riboprobe hybridized extensively with the photoreceptor inner segments, and the outer nuclear layer. Specific hybridization was also seen in a subpopulation of cells in the inner nuclear layer, and occasionally in cells of the ganglion cell layer (GCL). Recoverin-like immunoreactivity was observed in all photoreceptors, and in a subpopulation of bipolar cells. Very robust immunolabeling was observed in a small population of cells in the GCL. This study suggests that recoverin, or a recoverin-like protein, is produced by at least three different cell types in the human retina: photoreceptors, bipolars and rare cells in the ganglion cell layer.

Adult↗
PubMed2002

GABA(C) receptors modulate the rod-driven ERG b-wave of the skate retina.

Studies characterizing the types of GABA receptors present on cells isolated from the skate retina have allowed us to develop a working model of possible GABA interactions at the level of the outer plexiform layer (OPL). Earlier studies have shown an electrogenic GABA transport mechanism in horizontal cells presents a source of GABA in the OPL which could modulate feedback onto photoreceptors. GABA(A) receptors on Müller cells, or GABA(A) and/or GABA(C) receptors on bipolar cells. This model has been used for the interpretation of results of experiments in this study designed to test the role these interactions may exert on the electroretinogram (ERG). Simultaneous intracellular recording of the horizontal cell response (the S-potential) was used to monitor effects on photoreceptor transmitter release which would be altered if GABAergic photoreceptor feedback mechanisms were involved. Picorotoxin (50 microM), a chloride channel blocker which suppresses the responses of both GABA(A)Rs and GABA(C)Rs, reduced the ON (b-wave) component of the ERG substantially. Simultaneous intracellular horizontal cell recordings, however, showed no effect on their light-evoked response, suggesting that photoreceptor feedback is not involved in the picrotoxin effect on the ERG. On the other hand, even 100 microM bicuculline, a GABA(A)R antagonist produced no change in either the ERG or the horizontal cell response. This observation leads to the conclusion that the GABAARs on Miller cells and bipolar cells are not involved. Thus, there remains a distinct possibility that the ERG changes produced by picrotoxin are due to its ability to block the GABA(C)Rs on retinal bipolar cells.

Animals↗
PubMed2000

Peripherin/rds influences membrane vesicle morphology. Implications for retinopathies.

Peripherin/rds is an integral membrane glycoprotein found in the rim regions of vertebrate photoreceptor cell discs. Natural mutations of the encoding gene result in degenerative retinal disorders, such as retinitis pigmentosa. The retinal degeneration slow (rds) phenotype, observed in mice, is considered to be an appropriate model for peripherin/rds-mediated retinitis pigmentosa. Associated abnormalities in the outer segment of photoreceptor cells have implicated peripherin/rds in some aspect of disc morphology, yet it remains unclear whether such morphological effects are the cause or the result of this condition. Here we present the first direct evidence to support a role for peripherin/rds in maintaining the flattened vesicle morphology characteristic of photoreceptor outer segments. In vitro expression yields a 36-kDa immunoreactive species, which is inserted into membranes and undergoes N-glycosylation, inter- and intramolecular disulfide bonding, and dimerization. Electron microscopy reveals that peripherin/rds flattens microsomal vesicles. This effect appears to be dependent on disulfide bond formation but not N-glycosylation. The inability of two pathogenic peripherin/rds mutants (P216L and C165Y) to flatten membrane vesicles implicates such mutations as the primary cause of the retinal degeneration observed in retinitis pigmentosa.

Animals↗
PubMed2006

Defective development of photoreceptor membranes in a mouse model of recessive retinal degeneration.

Retinal neurodegeneration occurs in several inherited diseases. Some of the most severe disease alleles involve mutations at the C-terminus of rhodopsin, but in no case is the pathogenic mechanism leading to cell death well understood. We have examined a mouse model of recessive retinal degeneration caused by a knock-in of a human rhodopsin-EGFP fusion gene (hrhoG/hrhoG) at the rhodopsin locus. Whereas heterozygous mutant mice were indistinguishable from control mice, homozygous mutant mice had retinal degeneration. We hypothesized that degeneration might be due to aberrant rhodopsin signaling; however, inhibiting signaling by rearing mice in total darkness had no effect on the rate of degeneration. Using confocal and electron microscopy, we identified the fundamental defect as failed biogenesis of disk membranes, which is observed at the earliest stages of outer segment development. These results reveal that in addition to its role in transport and sorting of rhodopsin to disk membranes, rhodopsin is also essential for formation of disks.

Animals↗
PubMed1996

Kinetics of oxygen consumption and light-induced changes of nucleotides in solitary rod photoreceptors.

We made simultaneous measurements of light-induced changes in the rate of oxygen consumption (QO2) and transmembrane current of single salamander rod photoreceptors. Since the change of PO2 was suppressed by 2 mM Amytal, an inhibitor of mitochondrial respiration, we conclude that it is mitochondrial in origin. To identify the cause of the change of QO2, we measured, in batches of rods, the concentrations of ATP and phosphocreatine (PCr). After 3 min of illumination, when the QO2 had decreased approximately 25%, ATP levels did not change significantly; in contrast, the amount of PCr had decreased approximately 40%. We conclude that either the light-induced decrease of QO2 is not caused by an increase in [ATP] or [PCr], or that the light-induced change of [PCr] is highly heterogeneous in the rod cell.

Adenosine Triphosphate↗
PubMed2001

Rod vision: pathways and processing in the mammalian retina.

Bipolar cells in the mammalian retina are postsynaptic to either rod or cone photoreceptors, thereby segregating their respective signals into parallel vertical streams. In contrast to the cone pathways, only one type of rod bipolar cell exists, apparently limiting the routes available for the propagation of rod signals. However, due to numerous interactions between the rod and cone circuitry, there is now strong evidence for the existence of up to three different pathways for the transmission of scotopic visual information. Here we survey work over the last decade or so that have defined the structure and function of the interneurons subserving the rod pathways in the mammalian retina. We have focused on: (1) the synaptic ultrastructure of the interneurons; (2) their light-evoked physiologies; (3) localization of specific transmitter receptor subtypes; (4) plasticity of gap junctions related to changes in adaptational state; and (5) the functional implications of the existence of multiple rod pathways. Special emphasis has been placed on defining the circuits underlying the different response components of the AII amacrine cell, a central element in the transmission of scotopic signals.

Animals↗
PubMed1994

Expression of cyclic nucleotide-gated cation channels in non-sensory tissues and cells.

Using a combination of PCR based cloning and Northern blot analysis we have investigated the tissue expression of cyclic nucleotide-gated (CNG) cation channels in a variety of non-excitable tissues and cells. Partial sequences of all three known CNG channels and of an auxiliary subunit of the rod photoreceptor channel were determined. The expression of CNG channel genes is both tissue and species specific. Southern blot analysis with human genomic DNA revealed specific patterns of hybridization with probes derived from the different CNG channel types indicating that they are encoded by distinct genes. Analysis of human genomic sequences showed that all three genes are derived from a common ancestral gene and might have a similar gene structure. We were not able to identify additional genes encoding CNG channels. The CNG3 channel, which was originally cloned from bovine kidney may be expressed also in bovine cone photoreceptor cells. These data suggest that some of the effects of cGMP in peripheral tissues and cells might involve the activation of CNG channels.

Animals↗
PubMed1999

Two types of arrestins expressed in medaka rod photoreceptors.

Similar to visual arrestins of other vertebrates, two subtypes of medaka visual arrestins, KfhArr-R1 and KfhArr-C, are selectively expressed in rods and cones, respectively [Hisatomi et al. (1997) FEBS Lett. 411, 12-18]. We isolated a cDNA encoding the third arrestin, KfhArr-R2, from a medaka retinal cDNA library. Phylogenetic analysis of arrestin sequences suggests that KfhArr-R2 is classified into the rod arrestin subtype. In situ hybridization indicated that KfhArr-R2 mRNA is localized in most of the rod photoreceptors, suggesting that both KfhArr-R1 and -R2 are co-expressed in rods. Antisera against KfhArr-R2 recognized outer segments, but anti-KfhArr-R1 antisera reacted with cell bodies and synaptic termini in light-adapted rods. It seems likely that KfhArr-R1 and -R2 play different roles in rod photoreceptors.

Amino Acid Sequence↗
PubMed2004

The transcription factor Bhlhb4 is required for rod bipolar cell maturation.

Retinal bipolar cells are essential to the transmission of light information. Although bipolar cell dysfunction can result in blindness, little is known about the factors required for bipolar cell development and functional maturation. The basic helix-loop-helix (bHLH) transcription factor Bhlhb4 was found to be expressed in rod bipolar cells (RB). Electroretinograms (ERGs) in the adult Bhlhb4 knockout (Bhlhb4(-/-)) showed that the loss of Bhlhb4 resulted in disrupted rod signaling and profound retinal dysfunction resembling human congenital stationary night blindness (CSNB), characterized by the loss of the scotopic ERG b-wave. A depletion of inner nuclear layer (INL) cells in the adult Bhlhb4 knockout has been ascribed to the abolishment of the RB cell population during postnatal development. Other retinal cell populations including photoreceptors were unaltered. The timing of RB cell depletion in the Bhlhb4(-/-) mouse suggests that Bhlhb4 is essential for RB cell maturation.

Age Factors↗
PubMed2001

Synaptic vesicle alterations in rod photoreceptors of synaptophysin-deficient mice.

The abundance of the integral membrane protein synaptophysin in synaptic vesicles and its multiple possible functional contributions to transmitter exocytosis and synaptic vesicle formation stand in sharp contrast to the observed lack of defects in synaptophysin knockout mice. Assuming that deficiencies are compensated by the often coexpressed synaptophysin isoform synaptoporin, we now show that retinal rod photoreceptors, which do not synthesize synaptoporin either in wild-type or in knockout mice, are affected by the loss of synaptophysin. Multiple pale-appearing photoreceptors, as seen by electron microscopy, possess reduced cytoplasmic electron density, swollen mitochondria, an enlarged cell surface area, and, most importantly, a significantly reduced number of synaptic vesicles with an unusually bright interior. Quantification of the number of synaptic vesicles per unit area, not only in these, but also in all other rod terminals of knockout animals, reveals a considerable reduction in vesicles that is even more pronounced during the dark period, i.e., at times of highest synaptic activity. Moreover, activity-dependent reduction in synaptic vesicle diameter, typically occurring in wild-type mice, is not detected in knockout animals. The large number of clathrin-coated pits and vesicles in dark-adapted synaptophysin knockout mice is taken as an indication of compensatory usage of synaptophysin-independent pathway(s), and, conversely, in view of the overall reduction in the number of synaptic vesicles, as an indication for the presence of another synaptophysin-dependent synaptic vesicle recycling pathway. Our results provide in vivo evidence for the importance of the integral membrane protein synaptophysin for synaptic vesicle recycling and formation.

Action Potentials↗
PubMed1997

Transcriptional activation of the human rod cGMP-phosphodiesterase beta-subunit gene is mediated by an upstream AP-1 element.

During photoactivation retinal cGMP-phosphodiesterase (PDE) mediates signal transduction in the photoreceptor outer segments. Mutations in the beta-subunit gene of rod-specific PDE (beta-PDE) have been associated with inherited retinal degeneration in a number of species, including human. Here we have investigated the proximal upstream sequences that participate in transcriptional activation of this gene. Transient transfections demonstrated that the sequence from -72 to +53 bp contained sufficient information to direct high levels of gene expression in cells of retinal origin. Deletion or mutagenesis of an AP-1 motif present in this region caused 90-95% reduction in reporter gene expression. By gel mobility shift assay we demonstrated specific interactions between putative nuclear transcription factors and this AP-1 element. These findings indicate that the proximal AP-1 site in the human beta-PDE promoter is functionally relevant and necessary for transcriptional activation of this gene.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

Direct synaptic connections between rods and OFF cone bipolar cells in the rabbit retina.

Mammalian retinal circuits are broadly divided into rod and cone pathways, responsible for dark- and light-adapted vision, respectively. The classic rod pathway employs a single type of rod bipolar cell, which synapses with AII amacrine cells. AII amacrine cells then pass the signal to ON and OFF cone bipolar cells, respectively. Alternatively, rod signals may enter cones via gap junctions between rods and cones, and then pass from cones to cone bipolar cells. Thus, this second rod pathway does not utilize rod bipolar cells. Finally, in rodents, a third rod pathway, involving direct connections between rods and certain OFF cone bipolar cells, has been suggested. In this study, 56 OFF cone bipolar cells in the rabbit retina were dye-injected with Lucifer Yellow and their photoreceptor connections were examined by confocal microscopy in wholemount. The locations of rod and cone terminals were marked with antibodies to mGluR6 or synaptic proteins. Most OFF cone bipolar dendrites terminated at cone pedicles but some made potential contacts with rod spherules. The synaptic nature of these sites was confirmed by the presence of GluR2 receptors. All three OFF bipolar cell types had dendrites that terminated at rod spherules. However, approximately 80% of Ba2 and Ba3, but only 26% of Ba1 OFF cone bipolar cells made rod contacts. This variability suggests differential rod input to certain retinal pathways. In summary, we report anatomical evidence for direct connections between rods and OFF cone bipolar cells in a nonrodent mammal. Our data suggest that this alternative rod pathway may be a common feature of the mammalian retina.

Animals↗
PubMed2005

A simple and inexpensive light source for research in visual neuroscience.

Investigating the properties of light responsive neurons and their networks requires appropriate control of stimulus parameters, such as intensity, spectral composition, spatial and temporal profile. In the present paper, we describe how to build a simple, versatile and low-cost light source for use in visual neuroscience. The light source is a InGaN-based ultrabright light-emitting diode (LED), which may generate conventional light flashes as well as a variety of time varying stimuli to be used in quantitative studies of the visual system. In particular, with this instrument one may generate light stimuli sinusoidally modulated in time at frequencies ranging from 0.05 to 50 Hz, with less than 1% harmonic distortion at a contrast exceeding 85%. The relationship between applied voltage and energy emitted by the source is linear over an intensity range that exceeds 4.5 log-units, up to the full suppression of the light-sensitive currents in mammalian rods. The light source has minimal space requirement and does not generate appreciable radiating heat and hum, allowing its use for single cell work "in vitro" as well as for "in vivo" recording of the electroretinogram (ERG).

Animals↗
PubMed2005

Farnesylation of retinal transducin underlies its translocation during light adaptation.

G proteins are posttranslationally modified by isoprenylation: either farnesylation or geranylgeranylation. The gamma subunit of retinal transducin (Talpha/Tbetagamma) is selectively farnesylated, and the farnesylation is required for light signaling mediated by transducin in rod cells. However, whether and how this selective isoprenylation regulates cellular functions remain poorly understood. Here we report that knockin mice expressing geranylgeranylated Tgamma showed normal rod responses to dim flashes under dark-adapted conditions but exhibited impaired properties in light adaptation. Of note, geranylgeranylation of Tgamma suppressed light-induced transition of Tbetagamma from membrane to cytosol, and also attenuated its light-dependent translocation from the outer segment to the inner region, an event contributing to retinal light adaptation. These results indicate that, while the farnesylation of transducin is interchangeable with the geranylgeranylation in terms of the light signaling, the selective farnesylation is important for visual sensitivity regulation by providing sufficient but not excessive membrane anchoring of Tbetagamma.

Adaptation, Ocular↗
PubMedDate not supplied

Coupling pattern of S1 and S2 amacrine cells in the rabbit retina.

Previous studies have shown that indoleamine-accumulating cells (IACs) in the rabbit retina consist of two main cell types: S1 and S2 amacrine cells (Vaney, 1986; Sandell & Masland, 1986). Both cell types are wide-field GABA amacrine cells that make reciprocal synaptic contacts with rod bipolar cell terminals (Ehinger & Holmgren, 1979; Strettoi et al., 1990). We have examined the coupling pattern of S1 and S2 amacrine cells after the intracellular injection of Neurobiotin. Our results may be summarized as follows: (1) S1 amacrine cells were extensively coupled and their dendrites formed a network similar to but less dense than the matrix stained with an antibody to serotonin. (2) Morphological observations and cluster analysis, based on a scattergram, showed that the vast majority of coupled cells were S1 amacrine cells, accounting for approximately half of the total IACs. The rest of the uncoupled IACs were S2 amacrine cells. (3) Sometimes, two adjacent varicosities, one from an injected S1 and one from a coupled S1, contacted a single rod bipolar terminal. (4) S2 amacrine cells were also coupled but much less than the S1s. (5) Rarely, crossover coupling between S1 and S2 amacrine cells was observed. These results suggest that the extensive coupling between S1 amacrine cells, combined with a larger dendritic field, may contribute a wide-field component to the inhibitory surround of the rod pathway. By comparison, the smaller, weakly coupled S2 amacrine cells may provide a local component.

Amacrine Cells↗
PubMedDate not supplied

Effects of bicarbonate versus HEPES buffering on measured properties of neurons in the salamander retina.

Electrophysiological studies of the isolated retina involve perfusing the tissue with a physiological Ringer's. Organic pH buffers such as HEPES have become increasingly popular in recent years because for many purposes they offer a convenient and reliable alternative to the more traditional bicarbonate/CO2. In this paper, however, we report that important functional properties of rods, bipolar cells, and horizontal cells in the salamander, Ambystoma tigrinum, are sensitive to the choice of buffer and, in the case of horizontal cells, that sensitivity is acute. In bicarbonate/CO2 Ringer's, the dark potential of the horizontal cell was typically near -50 mV and saturating light caused it to hyperpolarize to about -75 mV. On switching to HEPES-buffered Ringer's at the same pH, horizontal cells depolarized in darkness to about -20 mV, close to the chloride equilibrium potential, and the kinetics of their light responses changed. The cone-driven components of light responses increased in size relative to rod-driven components. Saturating lights still hyperpolarized the cells to -75 mV, however. Horizontal cells, being coupled via gap junctions, form a syncytium and syncytial length constants, measured in bicarbonate/CO2 Ringer's, were generally in the range 150-225 microm. On switching to HEPES-buffered Ringer's, length constants increased substantially to 250-330 microm. All these changes were reversible. We discuss our findings within the context of the cell's ability to regulate its internal pH.

Ambystoma↗
PubMed2006

Nonvisual light responses in the Rpe65 knockout mouse: rod loss restores sensitivity to the melanopsin system.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin (OPN4), together with rods and cones, provide light information driving nonvisual light responses. We examined nonvisual photoreception in mice lacking RPE65, a protein that is required for regeneration of visual chromophore in rods and cones. Although Rpe65 knockouts retain a small degree of rod function, we show here that circadian phase shifting responses in Rpe65(-/-) mice are attenuated far beyond what has been reported for rodless/coneless mice. Furthermore, the number of melanopsin-immunoreactive perikarya and the extent of dendritic arborizations were decreased in Rpe65 knockout mice compared with controls. To assess the nature of the photoreceptive defect in Rpe65 null mice, we eliminated either rods or melanopsin from Rpe65(-/-) retinas by generating (i) Rpe65(-/-) mice carrying a transgene (rdta) that results in selective elimination of rods and (ii) double knockout Rpe65(-/-);Opn4(-/-) mice. Surprisingly, rod loss in Rpe65 knockout mice resulted in restoration of circadian photosensitivity. Normal photoentrainment was lost in Rpe65(-/-);Opn4(-/-) mice, and, instead, a diurnal phenotype was observed. Our findings demonstrate that RPE65 is not required for ipRGC function but reveal the existence of a mechanism whereby rods may influence the function of ipRGCs.

Animals↗