Biomedical subjects

M Kamermans

Publications and source records attributed to M Kamermans.

At least 19 recordsLinked to original sources

PubMed2005

The involvement of glutamate-gated channels in negative feedback from horizontal cells to cones.

Photoreceptors are the light sensitive cells in the retina. They project to horizontal cells and bipolar cells via a glutamatergic feed forward pathway. Horizontal cells are strongly electrically coupled and integrate in that way the input from the photoreceptors. Horizontal cells feedback to cones negatively. The combined signal from the photoreceptors and the horizontal cells is sent to the bipolar cells. The feedback pathway from horizontal cells to cones is thought to form the basis for the center/surround organization of bipolar cells. The nature of the feedback pathway is an issue of intense debate. It was thought for a long time that this feedback pathway was GABAergic, because cones have GABA-receptors and horizontal cells release GABA via a GABA-transporter working in the reversed direction. However, recently we showed in goldfish that horizontal cells feed back to cones via an alternative mechanism. In goldfish, negative feedback from horizontal cells to cones shifts the calcium current of the cone to more negative potentials. This feedback pathway is independent of GABA, since feedback cannot be blocked by either saturating concentrations of PTX, the GABA-transporter blocker SKF89976A, or application of GABA. The mechanism of negative feedback from horizontal cells to cones involves hemichannels located at the tips of the invaginating horizontal cells, just opposite to the calcium channels of the cones. Current flowing through these hemichannels changes the extracellular potential deep in the synaptic cleft and in that way modulates the calcium current of the cones. Such a modulation of the extracellular potential is called ephaptic. If negative feedback from horizontal cells to cones is indeed ephaptic, other channels present in the synapse should also be able to act as a current source, i.e., should also be able to change the output of the cone. We showed that glutamate-gated channels present at the tips of the horizontal cell dendrites can also mediate feedback responses. Surprisingly, although the glutamate-gated conductance of the horizontal cells is eight times the hemichannel conductance, glutamate-gated channels are not the major current source in negative feedback from horizontal cells to cones. In this chapter we present evidence that this is due to the more focal localization of the hemichannels, compared to a diffuse and extrasynaptic localization of the glutamate-gated channels.

Animals↗

PubMed2001

The dynamic characteristics of the feedback signal from horizontal cells to cones in the goldfish retina.

1. The dynamic properties of the microcircuitry formed by cones and horizontal cells in the isolated goldfish retina were studied. Cones project to horizontal cells and horizontal cells feed back to cones via a relatively slow negative feedback pathway. 2. The time constant of the feedback signal in cones and of the effect this feedback signal had on the responses of second-order neurons was determined using whole-cell patch clamp and intracellular recording techniques. 3. It was found that the feedback signal in cones had a time constant of around 80 ms, whereas the time constant of the effect this feedback signal had on the second-order neurons ranged from 36 to 116 ms. This range of time constants can be accounted for by the non-linearity of the Ca(2+) current in the cones. In depolarized cones, the feedback-mediated response in second-order neurons had a similar time constant to that of the direct light response of the cone, whereas in hyperpolarized cones, the time constant of the feedback-mediated response in second-order neurons was considerably larger. 4. Further, it was shown that there was no delay in the feedback pathway. This is in contrast to what has been deduced from the response properties of second-order neurons. In one type of horizontal cell, the responses to red light were delayed relative to the responses to green light. This delay in the second-order neurons can be accounted for by the interaction of the direct light response of the medium-wavelength-sensitive cones (M-cones) with the feedback response of the M-cones received from the horizontal cells.

Animals↗

PubMed2001

Hemichannel-mediated inhibition in the outer retina.

An essential feature of the first synapse in the retina is a negative feedback pathway from horizontal cells to cones. Here we show that at this synapse, connexin26 forms hemichannels on horizontal cell dendrites near the glutamate release site of the cones. Blocking these hemichannels hyperpolarizes horizontal cells, modulates the Ca2+ channels of the cones, and abolishes all feedback-mediated responses. We propose a feedback mechanism in which the activity of the Ca2+ channels and the subsequent glutamate release of the cones are modulated by a current through these hemichannels. Because the current through the hemichannels depends on the polarization of the horizontal cells, their activity modulates the output of the cones.

Animals↗

PubMed2001

The value of electrophysiology results in patients with epilepsy and vigabatrin associated visual field loss.

PURPOSE: To determine the value of electrophysiological findings in patients with temporal lobe epilepsy and to relate these findings to the amount of concentric contraction of the visual field and the use of vigabatrin. METHODS: Electro-retinograms and electro-oculograms were done on 30 patients, operated for temporal lobe epilepsy. The patients were divided into three groups: (A) concentric contraction of the visual field associated with a history of vigabatrin medication (15 patients), (B) normal visual field with vigabatrin use (11 patients) and (C) normal visual field without vigabatrin medication (4 patients). RESULTS: Electrophysiological abnormalities were found in 50% of the patients in group A. The Arden ratio of the EOG was lowered in 57%. Abnormalities in the ERG were found: b-wave implicit time photopic F was prolonged (50%), b-wave amplitudes scotopic B (53%), C (73%) and G (50%) and photopic H (50%) were diminished. The amount of visual field loss and the total dose of vigabatrin used, showed only slight correlation with the ERG and EOG. The use of vigabatrin during the ERG and EOG recording in group A, gave a higher b-wave amplitude scotopic G in 64% of cases. The a-wave implicit times scotopic G (73%) and photopic G (59%) and H (73%) were shortened in group B. CONCLUSION: EOG was abnormal in 57% in group A. ERG abnormalities could only be found in 50% of group A, mainly in the inner retina. Since also the total dose of vigabatrin and the amount of visual field loss did not really show a correlation with the electrophysiological findings and results of literature are not unanimous, electrophysiology does not appear at present to be a good method to detect patients with, or at risk of, vigabatrin associated visual field loss. Regularly performed visual field examination remains the cornerstone in screening.

Adult↗

PubMed2000

Immunocytochemical localization of the glutamate transporter GLT-1 in goldfish (Carassius auratus) retina.

Glutamate is the major excitatory neurotransmitter in the retina of vertebrates. Electrophysiological experiments in goldfish and salamander have shown that neuronal glutamate transporters play an important role in the clearance of glutamate from cone synaptic clefts. In this study, the localization of the glutamate transporter GLT-1 has been investigated immunocytochemically at the light and electron microscopical levels in the goldfish retina using a GLT-1-specific antibody. GLT immunoreactivity (IR) was observed at the light microscopical level in Müller cells, bipolar cells, the outer plexiform layer (OPL), and the inner plexiform layer (IPL). At the electron microscopical level, membrane-bound and cytoplasmic GLT-IR in the OPL was located in finger-like protrusions of the cone terminal located near the invaginating postsynaptic processes of bipolar and horizontal cells. GLT-IR was not observed in the vicinity of synaptic ribbons. This location of GLT-1 allows modulation of the glutamate concentration in the synaptic cleft, thereby shaping the dynamics of synaptic transmission between cones and second-order neurons. In the inner IPL, GLT-IR was observed in the cytoplasm and was membrane bound in mixed rod/cone bipolar cell terminals and cone bipolar cell terminals. The membrane-bound GLT-1 was generally observed at some distance from the synaptic ribbon. The morphology of the bipolar cell terminal together with the localization of GLT-1 suggests that at least these glutamate transporters are not primarily involved in rapid uptake of glutamate release by the bipolar cells. The GLT-IR in the cytoplasm of Müller cells was located throughout the entire goldfish retina from the outer limiting membrane to the inner limiting membrane. The location of GLT-1 in Müller cells is consistent with the role of Müller cells in converting glutamate to glutamine.

ATP-Binding Cassette Transporters↗

PubMed2000

Expression and localization of ionotropic glutamate receptor subunits in the goldfish retina--an in situ hybridization and immunocytochemical study.

The expression and distribution of AMPA, kainate and NMDA glutamate receptor subunits was studied in the goldfish retina. For the immunocytochemical localization of the AMPA receptor antisera against GluR2, GluR2/3 and GluR4 were used, and for in situ hybridization rat specific probes for GluR1 and GluR2 and goldfish specific probes for GluR3 and GluR4 were used. The localization of the low affinity kainate receptor and NMDA receptor was studied using antisera against GluR5-7 and NR1. All AMPA receptor subtypes were demonstrated to be present in the goldfish retina both by immunocytochemistry and in situ hybridization. In situ hybridization revealed expression of all AMPA receptors subunit at the inner border of the INL. Only GluR3 was also strongly expressed in the outer border of the INL. Some of the ganglion cells displayed a strong signal for GluR1, GluR3 and GluR4. GluR1-immunoreactivity was present in subsets of bipolar, amacrine, and ganglion cells. GluR2 and GluR2/3-immunoreactivity was mainly localized in the outer plexiform layer. GluR2 and GluR2/3-immunoreactivity are associated with the photoreceptor synaptic terminals. GluR4-immunoreactivity is present on Müller cells in the inner retina and on dendrites of bipolar cells in the OPL, whereas GluR5-7-immunoreactivity was prominently present on horizontal cell axon terminals. Finally, NR1-immunoreactivity was confined to amacrine cells, the inner plexiform layer and ganglion cells. This study shows that there is a strong heterogeneity of glutamate receptor subunit expression in the various layers of the retina. Of the AMPA receptor subunits GluR3 seems to be expressed the most widely in all layers with strong glutamatergic synaptic interactions whereas all the other subunits seem to have a more restricted expressed pattern.

Animals↗

PubMed2000

The nature of surround-induced depolarizing responses in goldfish cones.

Cones in the vertebrate retina project to horizontal and bipolar cells and the horizontal cells feedback negatively to cones. This organization forms the basis for the center/surround organization of the bipolar cells, a fundamental step in the visual signal processing. Although the surround responses of bipolar cells have been recorded on many occasions, surprisingly, the underlying surround-induced responses in cones are not easily detected. In this paper, the nature of the surround-induced responses in cones is studied. Horizontal cells feed back to cones by shifting the activation function of the calcium current in cones to more negative potentials. This shift increases the calcium influx, which increases the neurotransmitter release of the cone. In this paper, we will show that under certain conditions, in addition to this increase of neurotransmitter release, a calcium-dependent chloride current will be activated, which polarizes the cone membrane potential. The question is, whether the modulation of the calcium current or the polarization of the cone membrane potential is the major determinant for feedback-mediated responses in second-order neurons. Depolarizing light responses of biphasic horizontal cells are generated by feedback from monophasic horizontal cells to cones. It was found that niflumic acid blocks the feedback-induced depolarizing responses in cones, while the shift of the calcium current activation function and the depolarizing biphasic horizontal cell responses remain intact. This shows that horizontal cells can feed back to cones, without inducing major changes in the cone membrane potential. This makes the feedback synapse from horizontal cells to cones a unique synapse. Polarization of the presynaptic (horizontal) cell leads to calcium influx in the postsynaptic cell (cone), but due to the combined activity of the calcium current and the calcium-dependent chloride current, the membrane potential of the postsynaptic cell will be hardly modulated, whereas the output of the postsynaptic cell will be strongly modulated. Since no polarization of the postsynaptic cell is needed for these feedback-mediated responses, this mechanism of synaptic transmission can modulate the neurotransmitter release in single synaptic terminals without affecting the membrane potential of the entire cell.

Animals↗

PubMed2000

The open- and closed-loop gain-characteristics of the cone/horizontal cell synapse in goldfish retina.

Under constant light-adapted conditions, vision seems to be rather linear. However, the processes underlying the synaptic transmission between cones and second-order neurons (bipolar cells and horizontal cells) are highly nonlinear. In this paper, the gain-characteristics of the transmission from cones to horizontal cells and from horizontal cells to cones are determined with and without negative feedback from horizontal cells to cones. It is shown that 1) the gain-characteristic from cones to horizontal cells is strongly nonlinear without feedback from horizontal cells, 2) the gain-characteristic between cones and horizontal cells becomes linear when feedback is active, and 3) horizontal cells feed back to cones via a linear mechanism. In a quantitative analysis, it will be shown that negative feedback linearizes the synaptic transmission between cones and horizontal cells. The physiological consequences are discussed.

Animals↗

PubMed1999

The feedback pathway from horizontal cells to cones. A mini review with a look ahead.

The feedback pathway from HCs to cones forms the basis of the surround responses of the bipolar cells and is essential for the spectral opponency of horizontal cells. The nature of this feedback pathway is an issue of debate. Three hypothesis are presented in literature: (1) a GABAA-ergic feedback pathway; (2) a GABA-independent feedback pathway that modulates the Ca-current in cones; and (3) an electrical feedback pathway. In this review the evidence for the various pathways will be discussed. The conclusion is that the available evidence favors the hypothesis that feedback modulates the Ca-current in the cones in a GABA independent way. An alternative role of GABA in the outer plexiform layer is discussed and finally the functional consequences of the negative feedback pathway from horizontal cells to cones are presented.

Animals↗

PubMed1999

Effect of the tuberculostaticum ethambutol and stimulus intensity on chromatic discrimination in man.

In goldfish it has been shown that ethambutol shifts the threshold for wavelength discrimination without affecting the absolute sensitivity of the cones. In this study we demonstrate that a similar colour vision disturbance occurs in tuberculosis patients treated with ethambutol. After 2 months of ethambutol treatment, chromatic discrimination was measured with a computerized forced two choice (CD) test with isoluminant coloured stimuli and with three other colour vision tests: the Ishihara, the Oscar and the Lanthony Desaturated 15 Hue tests. The scores of the patient group (n = 19) on these four colour vision tests were compared with the scores of a group of control subjects (n = 33) and a group of congenital red/green colour-blind subjects (n = 5). A reduction of the stimulus intensity of 1 log unit caused a significant reduction in red/green chromatic discrimination, measured with the CD test in both, control subjects and patients. This intensity dependent reduction was significantly greater for patients than for controls. In this respect, man and goldfish behave similarly. Furthermore, the CD test showed the same ethambutol-induced reduction in chromatic discrimination at low intensity for the blue/green part of the spectrum. This has not been measured in goldfish. The origin of this ethambutol-induced colour vision disturbance must be at a post-photoreceptor site, because the Ishihara and Oscar tests, both designed to screen for photoreceptor-based, or primary red/green colour vision disturbances, did not discriminate between patients and control subjects. Thus, as in goldfish, we find that in patients ethambutol shifts the threshold for chromatic discrimination without changing the absolute sensitivity.

Adolescent↗

PubMed1999

Intrinsic cone adaptation modulates feedback efficiency from horizontal cells to cones.

Processing of visual stimuli by the retina changes strongly during light/dark adaptation. These changes are due to both local photoreceptor-based processes and to changes in the retinal network. The feedback pathway from horizontal cells to cones is known to be one of the pathways that is modulated strongly during adaptation. Although this phenomenon is well described, the mechanism for this change is poorly characterized. The aim of this paper is to describe the mechanism for the increase in efficiency of the feedback synapse from horizontal cells to cones. We show that a train of flashes can increase the feedback response from the horizontal cells, as measured in the cones, up to threefold. This process has a time constant of approximately 3 s and can be attributed to processes intrinsic to the cones. It does not require dopamine, is not the result of changes in the kinetics of the cone light response and is not due to changes in horizontal cells themselves. During a flash train, cones adapt to the mean light intensity, resulting in a slight (4 mV) depolarization of the cones. The time constant of this depolarization is approximately 3 s. We will show that at this depolarized membrane potential, a light-induced change of the cone membrane potential induces a larger change in the calcium current than in the unadapted condition. Furthermore, we will show that negative feedback from horizontal cells to cones can modulate the calcium current more efficiently at this depolarized cone membrane potential. The change in horizontal cell response properties during the train of flashes can be fully attributed to these changes in the synaptic efficiency. Since feedback has major consequences for the dynamic, spatial, and spectral processing, the described mechanism might be very important to optimize the retina for ambient light conditions.

Adaptation, Ocular↗

PubMed1997

Pseudo-immunolabelling with the avidin-biotin-peroxidase complex (ABC) due to the presence of endogenous biotin in retinal Müller cells of goldfish and salamander.

Immunodetection techniques are dependent on enzyme-protein conjugates for the visualisation of antigen-antibody complexes. One of the most widely used is the avidin-biotin-peroxidase complex (ABC) method. The present study demonstrates that direct treatment of goldfish and salamander retinal sections with ABC, followed by an incubation with the chromogenic substrate 3,3-diaminobenzidine tetrahydrochloride (DAB) and H2O2, manifested a punctate staining pattern across the neural retinae, presumably through binding of avidin to endogenous biotin. Incubation with a primary antiserum against biotin followed by immunoprocessing with the peroxidase--anti-peroxidase (PAP) method showed a pattern similar to the punctuate framework as detected with solo ABC-treated sections. Moreover, the ABC-DAB/H2O2 mediated pattern corresponded to the spatial orientation of Müller cells as identified by GFAP immunostaining. These findings indicate the presence of endogenous biotin in Müller cells and calls for caution in the application of the ABC method in immunotechniques in retinal research.

Animals↗

PubMed1996

Modulating wavelength discrimination in goldfish with ethambutol and stimulus intensity.

Wavelength discrimination in goldfish was measured behaviourally. Both acute application of ethambutol injected into the eye and chronic application by feeding the animals daily 25 mg ethambutol for 1 month had the same effect on wavelength discrimination in the range of 560-640 nm. This means that: (1) electrophysiological experiments, in which drug application is primarily acute, reflect the same disturbance as behavioural experiments, in which drug application is chronic; and that (2) the origin of the color vision defect must be retinal. Furthermore reduction in stimulus intensity by 2 log units caused, in control fish, a similar disturbance in wavelength discrimination as induced by ethambutol, whereas an increase of stimulus intensity by 2 log units abolished in ethambutol-fed fish the discrimination disturbance. These results indicate that ethambutol shifts the threshold for wavelength discrimination without changing the absolute sensitivity of the cone systems.

Animals↗

PubMed1996

Clearance of neurotransmitter from the cone synaptic cleft in goldfish retina.

Dendrites of bipolar and horizontal cells protrude deeply into the synaptic terminals of cones in goldfish retina. This arrangement gives the impression that the cone synaptic terminal surrounds a morphologically shielded compartment, the cone synaptic cleft, from which clearance of neurotransmitter by diffusion is limited. In this study the time constant of this clearance has been approached in two ways: (1) the morphological parameters determining the clearance (extracellular synaptic volume and leak area), were estimated using morphometric methods. These data were introduced into a diffusion model of the cone pedicle, yielding a time constant for the clearance of < 1 msec; (2) the time constant of the light onset response when the glutamate transporter in the cone was blocked with DL-threo-beta-hydroxyaspartate or dihydrokainate, was interpreted as the time constant of the clearance, yielding values of almost 650 msec compared to around 90 msec in control conditions. The decay time-constant of the Ca-dependent tail-currents in cones was used, as an approximation of the dynamics of the intracellular Ca-concentration and thus of the glutamate release by the cones. The decay time constant was about 800 msec. This suggests that the intracellular Ca-concentration in the synaptic terminal and hence the glutamate release by the cones drops with a similar large time constant. These results indicate that the cone pedicle in goldfish does not limit the clearance of neurotransmitters from the synaptic cleft and that the fast light onset response of horizontal cells under control conditions is due to activation of glutamate transporters by hyperpolarization of the cone membrane potential while the glutamate release drops slowly. The slow horizontal cell light onset response in beta-hydroxyaspartate or dihydrokainate may be due to a slow reduction of the glutamate release by the cones at light onset.

Animals↗

PubMed1996

Horizontal cells feed back to cones by shifting the cone calcium-current activation range.

We studied feedback from horizontal cells to cones in isolated goldfish retinae and found that surround stimuli evoke an inward current and a slowly developing outward current. The surround-evoked currents are blocked by the glutamate antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) and are, like horizontal cell responses, most effectively evoked by large stimuli. This indicates that the currents are caused by feedback from horizontal cells. The surround-evoked inward current is neither blocked by picrotoxin nor carried by chloride. Instead, it is carried by calcium, and it triggers a slowly developing calcium-dependent chloride current. We were unable to mimick the surround-evoked currents by modulating the extracellular GABA concentration. We conclude that when horizontal cells hyperpolarize they feed back to the cones by shifting the cone calcium-current activation range to more negative potentials. This type of feedback, directly targeted at the calcium current, scarcely influences the membrane potential of the receiving neuron, but effectively modulates its synaptic output.

Animals↗

PubMed1996

The size of the horizontal cell receptive fields adapts to the stimulus in the light adapted goldfish retina.

In this study the dynamic properties of goldfish horizontal cell (HC) receptive fields were evaluated. The size of HC receptive fields increases up to about 60 msec after stimulus onset, and then reduces to a smaller end value. They can therefore not adequately be described by the cable equation. Estimates of the length constant of the HC network based on the sustained responses are about 43% smaller than those based on the initial part of the response. This difference can be accounted for by feedback connections from HCs to cones because negative feedback reduces the receptive field size. The implication is that HCs are strongly coupled when the retina is stimulated more or less homogeneously but that they partly uncouple from the rest of the HC network when they are stimulated differently than the rest of the retina. The HCs thus generate a feedback signal based on the "local" stimulus properties. The size of the HC receptive fields depends on the spatial detail of the stimulus.

Adaptation, Ocular↗

PubMed1996

Modulation of horizontal cell receptive fields in the light adapted goldfish retina.

In the isolated goldfish retina, 700 nm background illumination increases the horizontal cell receptive field size, as measured with 565 nm slits of light, but decreases the receptive field size, when measured with 660 nm slits. These background-induced changes in receptive field size are absent when the depolarizing responses in bi- and triphasic horizontal cells are blocked by lowering the [Ca2+] in the Ringer's solution from 1.0 to 0.1 mM. These results cannot be explained by the linear properties of the horizontal cell layers, nor by slow adaptational processes, but are consistent with the concept that feedback from horizontal cells to cones modifies the horizontal cell receptive field properties.

Adaptation, Ocular↗

PubMed1995

Horizontal cells function normally in ethambutol-treated goldfish.

Ethambutol, a tuberculostatic drug, induces red-green colour vision defects in man and goldfish. The ethambutol-induced red-green colour vision defect in goldfish was argued to originate in the retina because after ethambutol application: (1) inhibitive interactions in red-green (double) opponent ganglion cells are lost [Van Dijk & Spekreijse, 1982 (Investigative Ophthalmology and Visual Science, 24, 128-133); Wietsma & Spekreijse, 1992 (Investigative Ophthalmology and Visual Science Suppl., 33, 1032)] and (2) the depolarizing responses to red light in the biphasic horizontal cells are reduced. To account for these findings Spekreijse, Wietsma and Neumeyer [(1991) Vision Research, 31, 551-562] suggested that ethambutol induced dark adaptation in the retina. In this paper the dark adaptation hypothesis is tested with the following results: (1) ethambutol changes only transiently the receptive field size and spectral sensitivity of horizontal cells; (2) the spectral characteristics of horizontal cells do not change in long-term ethambutol-treated goldfish; (3) formation of spinules on horizontal cell dendrites in cone terminals, a parameter for light adaptation, remains unaffected. Therefore we conclude that ethambutol does not induce functional dark adaptation of horizontal cells and that the ethambutol-induced red-green colour vision deficiency does not originate in the horizontal cell layers.

Action Potentials↗