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Synaptic transmission from horizontal cells to cones is impaired by loss of connexin hemichannels.

Klaassen LJ, Sun Z, Steijaert MN, Bolte P, Fahrenfort I, Sjoerdsma T, Klooster J, Claassen Y, Shields CR, Ten Eikelder HM, Janssen-Bienhold U, Zoidl G, McMahon DG, Kamermans M - PLoS Biol. (2011)

Bottom Line: A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized.A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback.To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones.

View Article: PubMed Central - PubMed

Affiliation: Research Unit Retinal Signal Processing, The Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.

ABSTRACT
In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina.

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Model simulations of feedback induced shift of Ca-current in wild-type and mutant zebrafish.Left: The simulated IV relations of  in control condition, DNQX, and KA, produced by the ephaptic feedback model [6]. Right: the DNQX- and KA-induced feedback currents. The value of  was varied from 100% (A) to 10% (C) of the wild-type value [6]. With reducing , the DNQX-induced feedback currents decrease and finally reverse. The KA-induced feedback currents only decrease with decreasing .
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pbio-1001107-g008: Model simulations of feedback induced shift of Ca-current in wild-type and mutant zebrafish.Left: The simulated IV relations of in control condition, DNQX, and KA, produced by the ephaptic feedback model [6]. Right: the DNQX- and KA-induced feedback currents. The value of was varied from 100% (A) to 10% (C) of the wild-type value [6]. With reducing , the DNQX-induced feedback currents decrease and finally reverse. The KA-induced feedback currents only decrease with decreasing .

Mentions: To test whether a reduced Ihemi could account for the decreased feedback in the mutants, we studied feedback-induced currents for different values of the hemichannel conductance (ghemi) in our quantitative feedback model (Figure 7) [6]. The DNQX-induced feedback currents were strongly reduced and eventually reverse with reduction of Ihemi (Figure 8). In contrast, the KA-induced feedback remained almost intact. Both the experimental data and the model show that feedback is affected in a highly asymmetrical manner. At about 40% ghemi, the model mimics the experimental findings (Figure 6Cii), suggesting the presence of some residual ghemi in the mutants.


Synaptic transmission from horizontal cells to cones is impaired by loss of connexin hemichannels.

Klaassen LJ, Sun Z, Steijaert MN, Bolte P, Fahrenfort I, Sjoerdsma T, Klooster J, Claassen Y, Shields CR, Ten Eikelder HM, Janssen-Bienhold U, Zoidl G, McMahon DG, Kamermans M - PLoS Biol. (2011)

Model simulations of feedback induced shift of Ca-current in wild-type and mutant zebrafish.Left: The simulated IV relations of  in control condition, DNQX, and KA, produced by the ephaptic feedback model [6]. Right: the DNQX- and KA-induced feedback currents. The value of  was varied from 100% (A) to 10% (C) of the wild-type value [6]. With reducing , the DNQX-induced feedback currents decrease and finally reverse. The KA-induced feedback currents only decrease with decreasing .
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3139627&req=5

pbio-1001107-g008: Model simulations of feedback induced shift of Ca-current in wild-type and mutant zebrafish.Left: The simulated IV relations of in control condition, DNQX, and KA, produced by the ephaptic feedback model [6]. Right: the DNQX- and KA-induced feedback currents. The value of was varied from 100% (A) to 10% (C) of the wild-type value [6]. With reducing , the DNQX-induced feedback currents decrease and finally reverse. The KA-induced feedback currents only decrease with decreasing .
Mentions: To test whether a reduced Ihemi could account for the decreased feedback in the mutants, we studied feedback-induced currents for different values of the hemichannel conductance (ghemi) in our quantitative feedback model (Figure 7) [6]. The DNQX-induced feedback currents were strongly reduced and eventually reverse with reduction of Ihemi (Figure 8). In contrast, the KA-induced feedback remained almost intact. Both the experimental data and the model show that feedback is affected in a highly asymmetrical manner. At about 40% ghemi, the model mimics the experimental findings (Figure 6Cii), suggesting the presence of some residual ghemi in the mutants.

Bottom Line: A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized.A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback.To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones.

View Article: PubMed Central - PubMed

Affiliation: Research Unit Retinal Signal Processing, The Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.

ABSTRACT
In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina.

Show MeSH
Related in: MedlinePlus