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At least 19 recordsLinked to original sources
PubMed1996

Molecular biology of retinal ganglion cells.

Retinal ganglion cells are the output neurons that encode and transmit information from the eye to the brain. Their diverse physiologic and anatomic properties have been intensively studied and appear to account well for a number of psychophysical phenomena such as lateral inhibition and chromatic opponency. In this paper, we summarize our current view of retinal ganglion cell properties and pose a number of questions regarding underlying molecular mechanisms. As an example of one approach to understanding molecular mechanisms, we describe recent work on several POU domain transcription factors that are expressed in subsets of retinal ganglion cells and that appear to be involved in ganglion cell development.

Animals↗
PubMed2006

Synthesis and characterization of a novel class of reducing agents that are highly neuroprotective for retinal ganglion cells.

Retinal ganglion cells (RGCs) undergo apoptosis after axonal injury, in part regulated by an intracellular superoxide anion burst, for which the target(s) are unknown. Shifting the RGC redox state towards reduction and preventing sulfhydryl oxidation is neuroprotective in vitro and in vivo, implying that one or more sulfhydryls on one or more critical proteins may be involved. We synthesized novel borane-protected analogues of the reductant tris(2-carboxyethyl)phosphine (TCEP) with the intent of increasing cell permeability and improving chemical stability, and tested their ability to increase RGC survival in vitro. Retinal ganglion cells of postnatal day 2-4 Long-Evans rats were retrogradely labeled with 4',6-diamidino-2-phenylindole (DAPI). At postnatal days 11-13 the animals were sacrificed, the retinas enzymatically dissociated and plated on poly-L-lysine-coated 96-well flat-bottomed tissue culture plates for 72 h in Neurobasal-A, B27 supplement lacking antioxidants, and TCEP, bis(3-propionic acid methyl ester)phenylphosphine borane complex (PB1), (3-propionic acid methyl ester)diphenylphosphine borane complex (PB2), or three commercially available phosphines. Viable DAPI-positive RGCs were identified by calcein-AM staining. At 72 h, PB1 was effective at rescuing acutely axotomized RGCs at concentrations from 1 nM to 100 microM. RGC survival with 1 nM PB1 was 174+/-12% of control (p=0.002). Another compound, PB2, rescued RGCs at 10 pM (177+/-24%; p=0.006) and 10 nM (251+/-34%; p=0.004) at 72 h. A PAMPA assay demonstrated that PB1 and PB2 were substantially more permeable than TCEP. These data demonstrate that modified reductants are effective RGC neuroprotectants at picomolar-nanomolar concentrations. We propose that these novel molecules may act by inhibiting the sulfhydryl oxidation effect of an intracellular superoxide burst.

Animals↗
PubMedDate not supplied

Intrinsic survival mechanisms for retinal ganglion cells.

Retinal ganglion cells (RGCs) undergo programmed cell death (apoptosis) after axonal injury. This cell death is mediated by several mechanisms, including deprivation of neurotrophic factors, alterations in gene expression, and production of reactive oxygen species. However, death of RGCs is delayed after axonal injury, and a significant number survive even after several days. This suggests that RGC death is not an immediate result of axonal injury, and that other pro-survival factors may play a role. While we and other researchers have focused on the mechanisms of cell death after axonal injury, it may be that determining the regulation of cell survival mechanisms may lead to innovative methods for neuroprotection. The final common pathway of glaucomatous optic neuropathy is RGC death, probably via damage to their axons occurring at or near the lamina cribrosa. Axonal injury leads directly (1) or indirectly (2) to the death of retinal ganglion cells. We and others have demonstrated that axotomy is associated with RGC apoptosis (3-7) as well as specific changes in expression of certain genes at the mRNA and protein level (8, 9). Reactive oxygen species may also be part of the pathway for RGC death (10, 11). We therefore hypothesize that axotomy leads to molecular events that are potentially destructive to RGCs, but also induces changes that are potentially protective against cellular injury. If this is the case, then RGC death from axonal injury would result not only from initiation of apoptosis, but also from failure of intrinsic neuroprotective mechanisms. It should therefore be theoretically possible to modulate these two classes of responses, and thus improve RGC cell survival after axotomy.

Animals↗
PubMed1988

Background light and the contrast gain of primate P and M retinal ganglion cells.

Retinal ganglion cells projecting to the monkey lateral geniculate nucleus fall into two classes: those projecting to the magnocellular layers of the nucleus (M cells) have a higher contrast gain to luminance patterns at photopic levels of retinal illumination than those projecting to the parvocellular layers (P cells). We report here that this difference in luminance contrast gain between M and P cells is maintained at low levels of mean retinal illumination. In fact, our results suggest that in the mesopic and scotopic ranges of mean illumination, the M-cell/magnocellular pathway is the predominant conveyor of information about spatial contrast to the visual cortex.

Animals↗
PubMed2002

Intrinsic physiological properties of cat retinal ganglion cells.

Retinal ganglion cells (RGCs) are the output neurons of the retina, sending their signals via the optic nerve to many different targets in the thalamus and brainstem. These cells are divisible into more than a dozen types, differing in receptive field properties and morphology. Light responses of individual RGCs are in large part determined by the exact nature of the retinal synaptic network in which they participate. Synaptic inputs, however, are greatly influenced by the intrinsic membrane properties of each cell. While it has been demonstrated clearly that RGCs vary in their intrinsic properties, it remains unclear whether this variation is systematically related to RGC type. To learn whether membrane properties contribute to the functional differentiation of RGC types, we made whole-cell current clamp recordings of RGC responses to injected current of identified cat RGCs. The data collected demonstrated that RGC types clearly differed from one another in their intrinsic properties. One of the most striking differences we observed was that individual cell types had membrane time constants that varied widely from approximately 4 ms (alpha cells) to more than 80 ms (zeta cells). Perhaps not surprisingly, we also observed that RGCs varied greatly in their maximum spike frequencies (kappa cells 48 Hz-alpha cells 262 Hz) and sustained spike frequencies (kappa cells 23 Hz-alpha cells 67 Hz). Interestingly, however, most RGC types exhibited similar amounts of spike frequency adaptation. Finally, RGC types also differed in their responses to injection of hyperpolarizing current. Most cell types exhibited anomalous rectification in response to sufficiently strong hyperpolarization, although alpha and beta RGCs showed only minimal, if any, rectification under similar conditions. The differences we observed in RGC intrinsic properties were striking and robust. Such differences are certain to affect how each type responds to synaptic input and may help tune each cell type appropriately for their individual roles in visual processing.

Action Potentials↗
PubMed2005

Microarray analysis of gene expression in adult retinal ganglion cells.

Retinal ganglion cells (RGCs) transfer visual information to the brain and are known to be susceptible to selective degeneration in various neuropathies such as glaucoma. This selective vulnerability suggests that these highly specialized neurons possess a distinct gene expression profile that becomes altered by neuropathy-associated stresses, which lead to the RGC death. In this study, to identify genes expressed predominantly in adult RGCs, a global transcriptional profile of purified primary RGCs has been compared to that of the whole retina. To avoid alterations of the original gene expression profile by cell culture conditions, we isolated RNA directly from adult RGCs purified by immunopanning without prior sub-cultivation. Genes expressed predominantly in RGCs included: Nrg1, Rgn, 14-3-3 family (Ywhah, Ywhaz, Ywhab), Nrn1, Gap43, Vsnl1, Rgs4. Some of these genes may serve as novel markers for these neurons. Our analysis revealed enrichment in genes controlling the pro-survival pathways in RGCs as compared to other retinal cells.

Animals↗
PubMed2005

Contrast adaptation in subthreshold and spiking responses of mammalian Y-type retinal ganglion cells.

Retinal ganglion cells adapt their responses to the amplitude of fluctuations around the mean light level, or the "contrast." But, in mammalian retina, it is not known whether adaptation arises exclusively at the level of synaptic inputs or whether there is also adaptation in the process of ganglion cell spike generation. Here, we made intracellular recordings from guinea pig Y-type ganglion cells and quantified changes in contrast sensitivity (gain) using a linear-nonlinear analysis. This analysis allowed us to measure adaptation in the presence of nonlinearities, such as the spike threshold, and to compare adaptation in subthreshold and spiking responses. At high contrast (0.30), relative to low contrast (0.10), gain reduced to 0.82 +/- 0.016 (mean +/- SEM) for the subthreshold response and to 0.61 +/- 0.011 for the spiking response. Thus, there was an apparent reduction in gain between the subthreshold and spiking response of 0.74 +/- 0.013. Control experiments suggested that the above effects could not be explained by an artifact of the intracellular recording conditions: extracellular recordings showed a gain change of 0.58 +/- 0.022. For intracellular recordings, negative current reduced the spike output but did not affect the gain change in the subthreshold response: 0.80 +/- 0.051. Thus, adaptation in the subthreshold response did not require spike-dependent conductances. We conclude that the contrast-dependent gain change in the spiking response can be explained by both a synaptic mechanism, as reflected by responses in the subthreshold potential, and an intrinsic mechanism in the ganglion cell related to spike generation.

Action Potentials↗
PubMed2003

Amplification of a reactive oxygen species signal in axotomized retinal ganglion cells.

Retinal ganglion cells (RGCs) undergo apoptosis after axonal injury. Elucidation of the sequence of intracellular events proximal to caspase activation may allow development of effective neuroprotective strategies. In this study, we explored the role that reactive oxygen species may have in signaling RGC apoptosis after axonal injury. Using the fluorescent probe dihydroethidium, we were able to measure intracellular superoxide anion production. We found that axotomized RGCs exposed to oxidative stress exhibited a secondary superoxide burst. The broad-spectrum caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethyl ketone did not block the burst, suggesting it is proximal to caspase activation, but it was inhibited by cycloheximide, consistent with a requirement for protein synthesis. These results are consistent with RGC axotomy inducing synthesis of one or more proteins that mediate oxidative amplification. This could be an early event in signaling of RGC apoptosis after axonal injury.

Amino Acid Chloromethyl Ketones↗
PubMed2002

Heterogeneous intrinsic firing properties of vertebrate retinal ganglion cells.

Retinal ganglion cells (RGCs) use their characteristic firing patterns to encode various aspects of visual information and carry them to the brain. It has been thought that the firing pattern of an RGC's light response is determined primarily by the time course and spatiotemporal interaction of the synaptic inputs. However, it is unclear whether there is a difference in intrinsic firing properties among RGCs that could contribute to the cell-to-cell distinction of the light response firing pattern. We investigated the intrinsic firing properties of isolated goldfish RGCs, minimizing cytoplasmic disturbance with a perforated-patch, whole-cell recording technique. In response to a 1-s depolarizing current step, the majority of the examined RGCs (n = 84) displayed sustained firing that lasted over 800 ms (n = 24; tonic RGCs) or transient firing accommodated within 200 ms of the step onset (n = 47; phasic RGCs). Tonic and phasic RGCs also differed in their firing frequency-current intensity dynamics. There was a significant difference in the soma sizes of phasic and tonic RGCs, indicating that some parts of these groups originate from distinct morphological subtypes. In the presence of extracellular Ba(2+) (1 mM), phasic RGCs displayed sustained firing and firing frequency-current intensity dynamics similar to those of tonic RGCs. Thus a Ba(2+)-sensitive ion current (I(Ba-s)) underlies the firing characteristics of phasic RGCs. Under voltage-clamp conditions, I(Ba-s) was identified as a low-threshold, noninactivating voltage-dependent K(+) current. Because of its slow kinetics (time constant of activation, approximately 100 ms), I(Ba-s) may confer a gradually increasing hyperpolarizing driving force during maintained excitatory stimulus, which eventually would result in firing accommodation. These findings suggest that RGCs have heterogeneous intrinsic firing properties that could aid synaptic inputs in shaping light responses.

Animals↗
PubMed2003

The effects of oxidative stress on mitochondrial transmembrane potential in retinal ganglion cells.

Retinal ganglion cells (RGCs) are central neurons that undergo apoptosis after axonal injury. As the relationship between mitochondrial and oxidative signaling of apoptosis in neuronal systems is unclear, we sought to achieve a better understanding of the interplay of these two pathways by investigating the effect of direct oxidative stress on mitochondrial membrane potential in cultured RGCs, as measured with the dual-emission probe JC-1. Treatment with hydrogen peroxide caused RGC mitochondrial depolarization. Several pharmacological treatments were used to define the mechanism. Whereas cycloheximide, tris(2-carboxyethyl)phosphine, and cyclosporin A were unable to prevent the depolarization, bongkrekic acid significantly reduced the severity of the depolarization. This suggests that the hydrogen peroxide-induced depolarization may act through mitochondrial permeability transition pore opening independent of thiol oxidation, and may be preventable under certain conditions.

Animals↗
PubMed2006

Muller glia induce retinal progenitor cells to differentiate into retinal ganglion cells.

Retinal progenitor cells could differentiate into various retinal cells that made cell-replacement therapy possible. Here, we investigated the role of cellular microenvironment on their regulation and differentiation and found that the percentage of proliferating cells and the percentage of retinal ganglion cells produced from them increased, when retinal progenitor cells were cocultured with Muller glia. Muller glia conditioned medium had the similar results. It is speculated that rather than traditional supportive roles, Muller glia may have an active regulatory role inducing retinal progenitor cells to proliferate and differentiate into ganglion cells by secreting some diffusible and membrane-associated factors. Identification of Muller glia-derived factors will be made to elucidate the molecular mechanisms of neurogenesis.

Animals↗
PubMed2000

Segregation of on and off bipolar cell axonal arbors in the absence of retinal ganglion cells.

Retinal cells that respond selectively to light onset or offset are segregated into On and Off pathways. Here, we describe the development of cone bipolar cells whose axonal arbors at maturity synapse onto ganglion cell dendrites confined to On and Off strata of the inner plexiform layer (IPL). In particular, we sought to determine whether the formation of this segregated pattern is dependent on the presence of ganglion cells. Developing bipolar cells were visualized using an antibody against recoverin, the calcium binding protein that labels On and Off cone bipolar cells in the adult rat retina. Recoverin-positive cells were apparent in the ventricular zone on the day of birth [postnatal day 0 (P0)], before bipolar cells begin to migrate to the inner nuclear layer. Two distinct strata were first apparent in the IPL at P8, with the Off pathway maturing earlier than the On pathway. There was no indication of exuberant bipolar cell projections. Throughout development, there were also a small number of recoverin-positive cells of unknown origin in the ganglion cell layer. To assess whether the formation of On and Off cone bipolar cell projections is dependent on the presence of ganglion cells, these target neurons were eliminated by unilateral section of the optic nerve. This was done on the day of birth, resulting in a total loss of ganglion cells 5-6 d before bipolar cell axons innervate the IPL. In retinas with optic nerve sections, On and Off cone bipolar cells were present, albeit at a lower than normal density, and the axonal arbors of these interneurons were organized into two distinct strata. This indicates that ganglion cells are not essential for the formation of segregated On and Off bipolar cell inputs. These results lend support to the hypothesis that specific ingrowth patterns of bipolar cell terminal arbors could regulate the formation of stratified retinal ganglion cell dendrites.

Age Factors↗
PubMed1991

Morphogenesis and territorial coverage by isolated mammalian retinal ganglion cells.

Identified retinal ganglion cells were isolated from postnatal cat retinas and their dendrites were removed by trituration and centrifugation. The denuded cells were placed in a cell culture system and allowed to reexpress dendritic arbors in the absence of afferent input, target tissue, and interactions with neighboring ganglion cells. The retinal ganglion cells were grown above a feeder layer of astrocytes on glass coverslips equipped with paraffin pedestals. The spatial patterns of the reexpressed neurites were quantitatively analyzed using a number of measures, including an estimate of the Hausdorff dimension, H, which was used as a scale-independent metric for how well the neurite patterns filled in a restricted spatial domain. As assessed by the estimation of the Hausdorff dimensions, the neurites from a single cell achieve uniform coverage of a restricted territory independent of the total neurite length or the total number of inter-branch-point segments. A comparison with H values of ganglion cells from the intact retina revealed a similar trend. These results suggest that these cultured ganglion cells can express an intrinsic growth strategy for the uniform coverage of a restricted territory. The arbors expressed in the culture system displayed a limited range of diameters and exhibited morphology similar to the alpha-, beta-, and gamma-ganglion cells of the intact retina in the absence of afferent input or the influences of neighboring cells and target tissue. Time-lapse video data revealed that individual cultured cells showed extensive dendritic remodeling during their growth; however, after about 3 d in culture, this remodeling did not appreciably affect the territorial coverage of a cell. In the intact retina, the existence of dendritic sheets that independently and uniformly sample visual space may result from this intrinsic ability to elaborate dendrites that uniformly cover or fill in a restricted territory.

Animals↗
PubMed2005

Stimulation of P2X7 receptors elevates Ca2+ and kills retinal ganglion cells.

PURPOSE: Retinal ganglion cells are known to express ionotropic P2X(7) receptors for ATP. Stimulation of these receptors in other cells can elevate Ca(2+) and sometimes lead to cell death. This study asked whether P2X(7) receptor stimulation alters the Ca(2+) levels and viability of retinal ganglion cells. METHODS: P2X(7) agonists were applied to retinal ganglion cells from neonatal rats loaded with fura-2 to examine their effect on intracellular Ca(2+) levels. The effect of P2X(7) receptor stimulation on cell viability was examined in rat retinal ganglion cells back-labeled with aminostilbamidine. RESULTS: The P2X(7) agonist benzoylbenzoyl adenosine triphosphate (BzATP) led to a large, sustained increase in Ca(2+). BzATP was >100-fold more effective than ATP at raising intracellular Ca(2+), when both agonists were applied at 10 microM. The response to BzATP was enhanced threefold by removal of extracellular Mg(2+), was dependent on extracellular Ca(2+), and was prevented by brilliant blue G (BBG). BzATP led to a concentration-dependent reduction in the number of cells with a median lethal dose (LD(50)) of 35 muM. Cell death was prevented by the P2X(7) antagonists BBG and oxidized ATP, but not by 30 microM suramin, consistent with the actions of the P2X(7) receptor. BzATP activated caspases in ganglion cells, but did not lead to membrane blebbing or increased permeability to Yo-Pro-1. The L-type Ca(2+) channel blocker nifedipine attenuated cell death, suggesting excessive Ca(2+) influx contributes to the lethal effects of BzATP. CONCLUSION: Short-term stimulation of the P2X(7) receptor can raise Ca(2+) in rat retinal ganglion cells, whereas sustained stimulation of the receptor can kill them.

Adenosine Triphosphate↗
PubMed1997

The role of Schwann cells during retinal ganglion cell regeneration induced by peripheral nerve transplantation.

PURPOSE: To investigate the key role of Schwann cells in retinal ganglion cell regeneration elicited by peripheral nerve autotransplantation. METHODS: Three kinds of autografts, Schwann-cell graft (intact sciatic nerve, consisting of living Schwann cells and their basal laminae). Schwann-cell-eliminated graft (consisting mainly of Schwann cell basal laminae) and partial Schwann-cell graft (consisting of basal laminae and diffusible factors secreted by Schwann cells) were prepared and autotransplanted to the adult rat optic nerve. The membrane specialization between regenerating axons and Schwann cells was observed by electron microscopy. The expression of cell adhesion molecules was demonstrated by Western blot analysis and immunohistochemistry. RESULTS: Retinal ganglion cell axons were observed to regenerate into the Schwann-cell graft in contact with Schwann cells but not into the Schwann-cell-eliminated graft. The regeneration was not observed in the empty basal laminae of the partial Schwann-cell graft. Most of regenerating axons contacted astrocytes in the optic nerve segment, and Schwann cells in the graft. At the interface of regenerating axon and Schwann cell, in addition to immunoreactivity of N-CAM and LI, short focal tight junctions were observed. CONCLUSIONS: These results suggested that viable Schwann cells are good substrate for retinal ganglion cell regeneration, the intimate contact with viable Schwann cell surface plays an important role in retinal ganglion cell regeneration, tight junctions, and cell adhesion molecules (LI, N-CAM) are observed between the regenerating axon and Schwann cell.

Animals↗
PubMed1995

The retinohypothalamic tract originates from a distinct subset of retinal ganglion cells.

The retinal ganglion cells giving rise to retinohypothalamic projections in the rat were identified using retrograde transport of horseradish peroxidase (HRP) or FluoroGold injected into the suprachiasmatic nucleus (SCN), and using transneuronal transport of the Bartha strain of the swine herpesvirus (PRV-Bartha). When PRV-Bartha is injected into one eye, it is taken up by retinal ganglion cells, replicated, transported to axon terminals in the SCN, and released. There the virus may take one, or both, of two paths to retinal ganglion cells in the contralateral eye: 1) uptake by SCN neurons, replication, and release from the neurons with uptake and retrograde transport in retinal afferents originating in the contralateral retina; 2) transneuronal passage through axo-axonic appositions between retinal afferents in the SCN with subsequent retrograde transport of virus to the contralateral retina. The ganglion cells thus labeled are a homogeneous population of small neurons (mean diameter, 12.8 +/- 2.2 microns and mean area, 81.8 +/- 21.8 microns 2) with sparsely branching dendrites that are widely distributed over the retina. This population is best identified when virus labeling of retinal projections in areas beyond the hypothalamus is eliminated by lateral geniculate lesions that transect the optic tract at its entry into the geniculate complex. The same population is labeled with retrograde tracers but, with both HRP and FluoroGold, other ganglion cells are labeled, presumably from uptake by fibers of passage, indicating that the virus is a more reliable marker for ganglion cells giving rise to retinohypothalamic projections. The ganglion cells identified correspond to a subset of type III, or W, cells.

Animals↗
PubMed1981

Outgrowth and maintenance of neurites from cultured goldfish retinal ganglion cells.

Single retinal ganglion cells obtained from goldfish retina are shown to support outgrowth of neurites. Processes up to 1 mm in length grow out over a two week period from cells identified as retinal ganglion cells on the basis of morphological criteria, in the absence of supporting elements. Prior crush of the optic nerve significantly enhances neuritic outgrowth. Fibers emerging from single cells often associate to form a single process. A tendency for characteristic clockwise patterning of neurite outgrowth from single cells is seen, similar to that obtained from retinal explants.

Animals↗
PubMed1998

Mechanisms of concerted firing among retinal ganglion cells.

Nearby retinal ganglion cells often fire action potentials in near synchrony. We have investigated the circuit mechanisms that underlie these correlations by recording simultaneously from many ganglion cells in the salamander retina. During spontaneous activity in darkness, three types of correlations were distinguished: broad (firing synchrony within 40-100 ms), medium (10-50 ms), and narrow (<1 ms). When chemical synaptic transmission was blocked, the broad correlations disappeared, but the medium and narrow correlations persisted. Further analysis of the strength and time course of synchronous firing suggests that nearby ganglion cells share inputs from photoreceptors conveyed through interneurons via chemical synapses (broad correlations), share excitation from amacrine cells via electrical junctions (medium), and excite each other via electrical junctions (narrow). It appears that the firing patterns in the optic nerve are strongly shaped by electrical coupling in the inner retina.

Action Potentials↗