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At least 235 records · Page 13Linked to original sources
PubMed2004

High mobility of vesicles supports continuous exocytosis at a ribbon synapse.

BACKGROUND: Most synapses release neurotransmitter as transient pulses, but ribbon synapses of sensory neurons support continuous exocytosis in response to maintained stimulation. We have investigated how the movement and retrieval of vesicles might contribute to continuous exocytosis at the ribbon synapse of retinal bipolar cells. RESULTS: Using a combination of total internal reflection fluorescence microscopy and fluorescence recovery after photobleaching, we found that the great majority of vesicles within 50-120 nm of the plasma membrane move in a random fashion with an effective diffusion coefficient of approximately 1.5 x 10(-2) microm(2) s(-1). Using confocal microscopy, we found that vesicles are similarly mobile across the whole terminal and that this motion is not altered by calcium influx or the actin cytoskeleton. We calculated that the cytoplasmic reservoir of approximately 300,000 vesicles would generate about 900 vesicle collisions/s against ribbons and 28,000 collisions/s against the surface membrane. The efficient resupply of vesicles to ribbons was confirmed by electron microscopy. A 1 min depolarization, releasing 500-1000 vesicles/s, caused a 70% reduction in the number of vesicles docked at the active zone without reducing the number of vesicles attached to ribbons or remote areas of the plasma membrane. These sites were not repopulated by retrieved vesicles because 80-90% of the recycled membrane was taken up into cisternae that pinched off from the surface. CONCLUSIONS: These results indicate that the random motion of cytoplasmic vesicles provides an efficient supply to the ribbon and plasma membrane and allows the maintenance of high rates of exocytosis without an equally rapid recycling of vesicles. The selective depletion of vesicles docked under ribbons suggests that the transfer of vesicles to the active zone limits the rate of exocytosis during maintained stimulation.

Animals↗
PubMed1998

Glutamate receptors: brain function and signal transduction.

Glutamate receptors are important in neural plasticity, neural development and neurodegeneration. N-methyl-d-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors act as glutamate-gated cation channels, whereas metabotropic receptors (mGluRs) modulate the production of second messengers via G proteins. Molecular studies from our and other laboratories indicated that NMDA receptors and mGluRs exist as multiple subunits (NMDAR1 and NMDAR2A-2D) and multiple subtypes (mGluR1-mGluR8). In light of the molecular diversity of glutamate receptors, we explored the function and intracellular signaling mechanisms of different members of glutamate receptors. In the visual system, retinal bipolar cells receive glutamate transmission from photoreceptors and contribute to segregating visual signals into ON and OFF pathways. The molecularly cloned mGluR6 is restrictedly expressed at the postsynaptic site of ON-bipolar cells in both rod and cone systems. Gene targeting of mGluR6 results in a loss of ON responses without changing OFF responses and severely impairs detecting visual contrasts. Since AMPA receptors mediate OFF responses in OFF-bipolar cells, two distinct types of glutamate receptors effectively operate for ON and OFF responses. mGluR1 and mGluR5 are both coupled to inositol triphosphate (IP3)/calcium signal transduction with an identical agonist selectivity. Single-cell intracellular calcium ([Ca2+]i) recordings indicated that glutamate evokes a non-oscillatory and oscillatory [Ca2+]i response in mGluR1-expressing and mGluR5-expressing cells, respectively. This difference results from a single amino acid substitution, aspartate of mGluR1 or threonine of mGluR5, at the G protein-interacting carboxy-terminal domains. Protein kinase C phosphorylation of the threonine of mGluR5 is responsible for inducing [Ca2+]i oscillations in mGluR5-expressing cells and cultured glial cells. Thus, the two closely related mGluR subtypes mediate diverging intracellular signaling in glutamate transmission.

Animals↗
PubMed1998

Submillisecond kinetics of glutamate release from a sensory synapse.

Exocytosis-mediated glutamate release from ribbon-type synaptic terminals of retinal bipolar cells was studied using AMPA receptors and simultaneous membrane capacitance measurements. Release onset (delay <0.8 ms) and offset were closely tied to Ca2+ channel opening and closing. Asynchronous release was not copious and we estimate that there are approximately 5 Ca2+ channels per docked synaptic vesicle. Depending on Ca2+ current amplitude, release occurred in a single fast bout or in two successive bouts with fast and slow onset kinetics. The second, slower bout may reflect a mobilization rate of reserve vesicles toward fusion sites that is accelerated by increasing Ca2+ influx. Bipolar cell synaptic ribbons thus are remarkably versatile signal transducers, capable of transmitting rapidly changing sensory input, as well as sustained stimuli, due to their large pool of releasable vesicles.

Animals↗
PubMed1992

Substance P modulates calcium current in retinal bipolar neurons.

Retinal bipolar cells are non-spiking interneurons that relay information from photoreceptors to amacrine and ganglion cells. In turn, bipolar cells receive extensive synaptic feedback from amacrine cells, some of which contain neuropeptides, including substance P. We have examined the effect of substance P on single bipolar neurons isolated from goldfish retina and find that substance P (0.1-1 nM) produced a voltage-dependent inhibition of calcium current in these cells. The inhibition was strongest at negative potentials, with the peak suppression occurring at -20 to -30 mV; at potentials positive to 0 mV, there was little effect on calcium current. Thus, the net effect was to shift the voltage range of activation of calcium current toward more positive potentials. The inhibition of calcium current by substance P required GTP in the patch pipette and was blocked by internal GDP-beta-S. Similar effects on calcium current were observed with somatostatin and metenkephalin, which are also found in amacrine cells.

Animals↗
PubMed2000

Image processing experiments for computer-based three-dimensional reconstruction of neurones from electron micrographs from serial ultrathin sections.

This study examined an image processing technique that uses a computer to reconstruct a three-dimensional image of neurones from electron micrographs of serial ultrathin sections. The major problems involved were: (a) a distortion of features in electron micrographs; (b) a significant change of cross-section features of neurones in electron micrographs of neighbouring sections; and (c) disagreement between the electron microscopic section face and the coordinate plane desired for the reconstruction. Electron micrographs of a retinal bipolar cell stained with a biotinylated tracer were used. We corrected the distortion of features by means of a warp, a widely used algorithm in morphing image processing. The change of features between neighbouring electron micrographs was minimized by filling the gaps with an interpolated image produced by a dissolve, another algorithm in morphing, as well as the warp. The distortion of the three-dimensional reconstructed image made by piling up features was corrected by making the image with a wire frame model. Furthermore, in order to estimate a closed contour of features, an active contour model, Snakes, was applied to the electron microscope features. Snakes successfully detected the contour of the target feature, but in some electron microscope images broke into the target feature.

Algorithms↗
PubMed2000

Mammalian achaete-scute and atonal homologs regulate neuronal versus glial fate determination in the central nervous system.

Whereas vertebrate achaete-scute complex (as-c) and atonal (ato) homologs are required for neurogenesis, their neuronal determination activities in the central nervous system (CNS) are not yet supported by loss-of-function studies, probably because of genetic redundancy. Here, to address this problem, we generated mice double mutant for the as-c homolog Mash1 and the ato homolog Math3. Whereas in Mash1 or Math3 single mutants neurogenesis is only weakly affected, in the double mutants tectal neurons, two longitudinal columns of hindbrain neurons and retinal bipolar cells were missing and, instead, those cells that normally differentiate into neurons adopted the glial fate. These results indicated that Mash1 and Math3 direct neuronal versus glial fate determination in the CNS and raised the possibility that downregulation of these bHLH genes is one of the mechanisms to initiate gliogenesis.

Animals↗
PubMed2003

Identification of the gene and the mutation responsible for the mouse nob phenotype.

PURPOSE: The available evidence indicates that the naturally occurring mouse mutant nob (no b-wave) provides an animal model for the complete form of human X-linked congenital stationary night blindness (CSNB1). The goals of the present study were to identify the nob gene defect, to characterize the expression pattern of the involved gene, and to assess visual sensitivity in nob mice. METHODS: Positional cloning, screening of candidate genes, and sequencing were used to identify the nob gene. The expression pattern of the nyx gene was examined with Northern blot analysis and in situ hybridization. Visual sensitivity was measured with an active avoidance behavioral test. RESULTS: The nob phenotype is caused by an 85-bp deletion in the mouse nyx gene, which encodes the nyctalopin protein. Expression of nyx was most abundant in the retina and, in particular, in the inner nuclear layer. The nyctalopin protein contains 11 leucine-rich repeats and is flanked by cysteine rich regions, which identifies it as a member of the small leucine rich proteoglycan family. Behavioral testing shows that nob mice have a significant decrease in visual sensitivity. CONCLUSIONS: The nob mouse is a model for human CSNB1. This model will be useful in defining the role of nyctalopin in signal transmission between photoreceptors and retinal bipolar cells.

Amino Acid Sequence↗
PubMed2006

Efficiency of synaptic transmission of single-photon events from rod photoreceptor to rod bipolar dendrite.

A rod transmits absorption of a single photon by what appears to be a small reduction in the small number of quanta of neurotransmitter (Q(count)) that it releases within the integration period ( approximately 0.1 s) of a rod bipolar dendrite. Due to the quantal and stochastic nature of release, discrete distributions of Q(count) for darkness versus one isomerization of rhodopsin (R*) overlap. We suggested that release must be regular to narrow these distributions, reduce overlap, reduce the rate of false positives, and increase transmission efficiency (the fraction of R* events that are identified as light). Unsurprisingly, higher quantal release rates (Q(rates)) yield higher efficiencies. Focusing here on the effect of small changes in Q(rate), we find that a slightly higher Q(rate) yields greatly reduced efficiency, due to a necessarily fixed quantal-count threshold. To stabilize efficiency in the face of drift in Q(rate), the dendrite needs to regulate the biochemical realization of its quantal-count threshold with respect to its Q(count). These considerations reveal the mathematical role of calcium-based negative feedback and suggest a helpful role for spontaneous R*. In addition, to stabilize efficiency in the face of drift in degree of regularity, efficiency should be approximately 50%, similar to measurements.

Animals↗
PubMed1998

Two types of calcium currents of the mouse bipolar cells recorded in the retinal slice preparation.

In the vertebrate retina, the bipolar cell makes reciprocal synapses with amacrine cells at the axon terminal. It has been postulated that amacrine cells may control the transmitter release from bipolar cells by modulating their calcium currents (ICa). To clarify this possibility calcium currents were studied in bipolar cells of the mouse retina using a slice preparation. ICa was identified by voltage clamp protocols, ionic substitution and pharmacological tools. Depolarization to -30 mV from a holding voltage of -80 mV induced an inward current consisting of an initial transient and a long-lasting sustained component. The transient component was inactivated by holding the membrane at more positive voltages. Addition of 100 microM nifedipine suppressed the sustained component, leaving the transient component almost intact. The sustained component was enhanced when external solution contained 0.1 microM Bay K 8644 or when the external Ca2+ was substituted by equimolar Ba2+. Omega-conotoxin (10 microM omega-ctxn GVIA) did not alter either component. We concluded that the transient component is a low-voltage activated T-type ICa, while the sustained component is a high-voltage activated L-type ICa. T-type ICa was recorded in all cells tested, while L-type ICa was found only in cells that retained axon terminals ramifying in the inner plexiform layer. Thus, it is highly likely that L-type ICa is generated at the axon terminal and contributes to the transmitter release from the bipolar cell. The present results confirm that in addition to the T-type ICa that had been previously described, bipolar cells of the mammalian retina also contain L-type ICa similar to the one that has been reported in bipolar cells of the goldfish. The use of retinal slice preparation allowed us to record this current that was not seen previously in the dissociated mouse bipolar cells.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2006

Inner retinal mechanisms engaged by retinal electrical stimulation.

PURPOSE: Retinal prosthetic devices are being developed to bypass degenerated retinal photoreceptors by directly activating retinal neurons with electrical stimulation. However, little is known about retinal activity during such stimulation. METHODS: Whole cell patch-clamp recordings were obtained from ganglion and bipolar cells in the salamander retinal slice preparation. A stimulating electrode was positioned at the vitreal surface of the slice. RESULTS: Brief pulses of cathodic current evoked transient inward currents in ganglion cells arising from action potentials. Longer pulses (>5 milliseconds) also evoked sustained inward currents in ganglion cells that appeared synaptic in origin because, unlike transient currents, sustained currents were blocked by inhibiting synaptic transmission with Cd2+. These synaptic currents reversed around ECl and were blocked by picrotoxin, strychnine, or both, suggesting they were mediated by GABAa/c and glycine receptors. Synaptic currents were also blocked by the NMDA antagonist MK801 and the KA/AMPA antagonist NBQX, suggesting that epiretinal stimulation evoked glutamate release from bipolar cells, which in turn stimulated the release of GABA and glycine from amacrine cells. Sustained currents were also evoked by epiretinal stimulation in bipolar cells. These currents reversed near ECl and were blocked by picrotoxin, suggesting they arose from GABAa/c receptors. CONCLUSIONS: Pulse duration is an important parameter for effective activation of the inner retina by epiretinal stimulation. Brief pulses evoke action potentials only in ganglion cells. However, longer pulses also evoke sustained synaptic currents by stimulating glutamate release from bipolar cell terminals, which, in turn, evokes the release of GABA and glycine from amacrine cells.

Action Potentials↗
PubMed1999

Rapid desensitization converts prolonged glutamate release into a transient EPSC at ribbon synapses between retinal bipolar and amacrine cells.

The mechanisms underlying the conversion of prolonged glutamate release from ribbon synapses in bipolar cells to sustained and transient excitatory postsynaptic responses in identified retinal amacrine cells were studied in tiger salamander (Ambystoma tigrinum) retina. A retina slice preparation with whole cell patch recording techniques under voltage- and current-clamp conditions was used to assay the electrical properties of bipolar and amacrine cells. Amacrine cells were categorized into two basic forms: (i) transient amacrine cells that respond to a step of light with a burst of spikes only at the transitions of the step; and (ii) sustained amacrine cells that respond with continuous spiking during the entire light step. The two cell types each had a characteristic morphology: transient amacrine cells possessed wide dendritic fields (chi = 375 microns), while sustained cells had much more narrowly confined dendritic fields (chi = 85 microns). Whole cell voltage-gated currents of the transient and sustained cell types were not significantly different. Both cell types had spikes that were sensitive to tetradotoxin (TTX, 0.3 microM) with voltage deflections of up to 100 mV. Light-evoked excitatory synaptic currents relaxed rapidly in transient neurons (tau 1/2 = 100 ms) and more slowly in sustained neurons (tau 1/2 = 1.2 s). EPSCs in both cells reversed near 0 mV. Rapid application of glutamate or kainate elicited rapidly desensitizing ionic currents (tau 1/2 = 85 ms) followed by a slowly desensitizing component. Cyclothiazide, a drug that eliminates rapid desensitization, lengthened the time course of the glutamate gated current from tau 1/2 = 85 ms to about 3 s, and the relaxation kinetics of the glutamatergic EPSC from tau 1/2 = 85 ms to about 1.0 s. These data suggest that a key determinant in forming transient versus sustained responses in amacrine cells of vertebrate retina is the differences in their excitatory, glutamatergic synaptic inputs, and that rapid desensitization of glutamate receptors plays a role in converting the presynaptic signal associated with sustained glutamate release into a postsynaptic, transient signal at the ribbon synapse.

Action Potentials↗
PubMedDate not supplied

Responses of rod bipolar cells isolated from dogfish retinal slices to concentration-jumps of glutamate.

Rod on-bipolar cell light responses are mediated by a class of metabotropic glutamate receptor which is coupled via a G-protein to the control of a cGMP cascade, with cGMP acting to open cation channels, whilst off-bipolar cells possess ionotropic glutamate receptors. Whole-cell voltage-clamp recordings were obtained from on- and off-bipolar cells of dark-adapted dogfish retinal slices, identified by their light responses. Isolated cells were exposed to concentration-jumps of glutamate. At negative voltage-clamp potentials, on-bipolar cells responded to glutamate with outward currents with a mean delay of 10.8 ms, whilst off-bipolar cells responded with inward currents without any delay. Neither cell type showed desensitization to applied steps of glutamate. The dose-response relation for on-bipolar cells showed no gradual saturation, but increased linearly with a sharp cutoff above 200 microM glutamate. This dose-response relation could be fitted with a theoretical expression assuming Michaelis-Menten kinetics for the action of glutamate on receptors and a linear relation between the concentration of receptors bound to glutamate and the fall in cGMP this induces. The dose-response relation of off-bipolar cells showed saturation with a limiting slope of 2 at low glutamate concentrations, suggesting that two molecules of glutamate are required to open each channel by a cooperative mechanism. The glutamate receptor coupled cGMP cascade of rod on-bipolar cells can account for high synaptic voltage gain.

Animals↗
PubMed2001

Retinal anti-bipolar cell antibodies in a patient with paraneoplastic retinopathy and colon carcinoma.

PURPOSE: To describe clinical, electrophysiologic, and immunologic features of a unique paraneoplastic retinopathy with characteristics of cancer-associated and melanoma-associated retinopathy. METHODS: Serial assessment of clinical visual function, electroretinography, and assays of anti-retinal antibodies. RESULTS: A 51-year-old woman with progressive visual glare for 1 year had normal visual acuity and color vision, paracentral scotomas, and a normal-appearing retina. Electroretinography revealed no responses of the right eye and attenuated responses of the left eye, especially those recorded under scotopic conditions. Anti-bipolar antibodies were detected. Subsequent evaluation uncovered adenocarcinoma of the colon. Several months after resection of the tumor and chemotherapy, no evidence existed of cancer or anti-bipolar cell antibodies, and electroretinography responses were markedly improved. CONCLUSION: The presence of anti-bipolar cell antibodies in a patient with retinal dysfunction is not specific of melanoma-associated retinopathy. Effective treatment of cancer may result in elimination of associated anti-retinal antibodies and improved retinal function.

Adenocarcinoma↗
PubMed1987

Morphometric analysis of serotoninergic bipolar cells in the retina and its implications for retinal image processing.

The entire population of retinal serotoninergic bipolar cells in the turtle Pseudemys scripta elegans was labeled by immunocytochemical methods. This allowed a systematic analysis to be made of the morphological variabilities among a functionally homogeneous neuronal population. The analyzed morphological characteristics included: size of the Landolt club, size of the soma, lateral extension of the ramification within the outer plexiform layer, course of the axon across the inner nuclear layer, pattern of the axonal ramification within the inner plexiform layer, lateral extension of these ramifications, and density of the cells. Whereas characteristics 1-4 and 7 show a morphological variability strictly related to the location of the bipolar cell with respect to the visual streak, a fovealike structure, characteristics 5 and 6 show no such correlation. The size of the soma increases by a factor of 4 from the visual streak toward the periphery. The area covered by the ramification in the OPL increases from 330 micron 2 at the visual streak to 50,000 microns 2 at the dorsal and ventral edges of the retina. The coverage factor remains the same throughout the retina, as well as the area covered by the ramifications in the IPL, which is about 2,000 microns 2. At the visual streak and at 110 degrees ventral and 68 degrees dorsal of the visual streak, the bipolar axons cross the INL perpendicularly. In between the axons take an oblique course leading to an axon-induced shift between input and output of up to 250 microns.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Different functional types of bipolar cells use different gap-junctional proteins.

Rod signals are transmitted to ON retinal ganglion cells by means of gap junctions between AII amacrine cells and ON bipolars. The AII amacrine cells are known to express connexin36 (Cx36), but previous studies of Cx36 in ON cone bipolars have been ambiguous. Here, we studied bipolar cells in a transgenic mouse line that expresses high levels of green fluorescent protein (GFP) in one type of ON cone bipolar cell. We found strong Cx36 immunostaining in the axon terminals of the GFP-labeled type 357 bipolar cells in both vertical sections and whole mounts of the retina. This finding was confirmed by single-cell immunostaining and single-cell reverse transcription-PCR (RT-PCR). As reported previously (Maxeiner et al., 2005), Cx45 was found in some ON bipolar cells, but RT-PCR showed Cx36 and not Cx45 to be expressed by the type 357 bipolar cells. Some of the remaining GFP-negative bipolar cells expressed Cx45 but not Cx36. It appears that different types of ON cone bipolar cells express different connexins at their gap junctions with AII amacrine cells.

Amacrine Cells↗
PubMedDate not supplied

Reciprocal inhibition of voltage-gated potassium currents (I K(V)) by activation of cannabinoid CB1 and dopamine D1 receptors in ON bipolar cells of goldfish retina.

Cannabinoid CB1 receptor (via Gs) and dopamine D2 receptor (via Gi/o) antagonistically modulate goldfish cone membrane currents. As ON bipolar cells have CB1 and D1 receptors, but not D2 receptors, we focused on whether CB1 receptor agonist and dopamine interact to modulate voltage-dependent outward membrane K+ currents I K(V) of the ON mixed rod/cone (Mb) bipolar cells. Whole-cell currents were recorded from Mb bipolar cells in goldfish retinal slices. Mb bipolar cells were identified by intracellular filling with Lucifer yellow. The bath solution was calcium-free and contained 1 mM cobalt to block indirect calcium-dependent effects. Dopamine (10 microM) consistently increased I K(V) by a factor of 1.57 +/- 0.12 (S.E.M., n = 15). A CB receptor agonist, WIN 55212-2 (0.25-1 microM), had no effect, but 4 microM WIN 55212-2 suppressed I K(V) by 60%. If I K(V) was first increased by 10 microM dopamine, application of WIN 55212-2 (0.25-1 microM) reversibly blocked the effect of dopamine even though these concentrations of WIN 55212-2 had no effect of their own. If WIN 55212-2 was applied first and dopamine (10 microM) was added to the WIN-containing solution, 0.1 microM WIN 55212-2 blocked the effect of dopamine. All effects of WIN 55212-2 were blocked by coapplication of SR 141716A (CB1 antagonist) and pretreatment with pertussis toxin (blocker of Gi/o) indicating action via CB1 receptor activation of G protein Gi/o. Coactivation of CB1 and D1 receptors on Mb bipolar cells produces reciprocal effects on I K(V). The CB1-evoked suppression of I K(V) is mediated by G protein Gi/o, whereas the D1-evoked enhancement is mediated by G protein Gs. As dopamine is a retinal "light" signal, these data support our notion that endocannabinoids function as a "dark" signal, interacting with dopamine to set retinal sensitivity.

Animals↗