Connexin50 couples axon terminals of mouse horizontal cells by homotypic gap junctions

Dorgau, Birthe; Herrling, Regina; Schultz, Konrad; Greb, Helena; Segelken, Jasmin; Ströh, Sebastian; Bolte, Petra; Weiler, Reto; Dedek, Karin; Janssen‐Bienhold, Ulrike

doi:10.1002/cne.23779

Cited by 22 publications

(14 citation statements)

References 51 publications

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“…Similarly, retinal morphology of Cx57 +/lacZ heterozygotes and Cx57 lacZ/lacZ nulls was reported to be normal ( Shelley et al, 2006 ; Janssen-Bienhold et al, 2009 ), as was the synaptic morphology between photoreceptors and horizontal cells ( Shelley et al, 2006 ). Recently, another connexin isoform (Cx50), which couples axon terminals of mouse horizontal cells, was reported ( Dorgau et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Targeted Deletion of Vesicular GABA Transporter from Retinal Horizontal Cells Eliminates Feedback Modulation of Photoreceptor Calcium Channels

Hirano

Boulter

et al. 2016

eNeuro

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The cellular mechanisms underlying feedback signaling from horizontal cells to photoreceptors, which are important for the formation of receptive field surrounds of early visual neurons, remain unsettled. Mammalian horizontal cells express a complement of synaptic proteins that are necessary and sufficient for calcium-dependent exocytosis of inhibitory neurotransmitters at their contacts with photoreceptor terminals, suggesting that they are capable of releasing GABA via vesicular release. To test whether horizontal cell vesicular release is involved in feedback signaling, we perturbed inhibitory neurotransmission in these cells by targeted deletion of the vesicular GABA transporter (VGAT), the protein responsible for the uptake of inhibitory transmitter by synaptic vesicles. To manipulate horizontal cells selectively, an iCre mouse line with Cre recombinase expression controlled by connexin57 (Cx57) regulatory elements was generated. In Cx57-iCre mouse retina, only horizontal cells expressed Cre protein, and its expression occurred in all retinal regions. After crossing with a VGAT flox/flox mouse line, VGAT was selectively eliminated from horizontal cells, which was confirmed immunohistochemically. Voltage-gated ion channel currents in horizontal cells of Cx57-VGAT Ϫ/Ϫ mice were the same as Cx57-VGAT ϩ/ϩ controls, as were the cell responses to the ionotropic glutamate receptor agonist kainate, but the response to the GABA A receptor agonist muscimol in Cx57-VGAT Ϫ/Ϫ mice was larger. In contrast, the feedback inhibition of photoreceptor calcium channels, which in control animals is induced by horizontal cell depolarization, was completely absent in Cx57-VGAT Ϫ/Ϫ mice. The results suggest that vesicular release of GABA from horizontal cells is required for feedback inhibition of photoreceptors. Key words: Ca channels; Cx57-iCre; GABA receptors; inhibitory feedback; retinal horizontal cells; synaptic vesicles Significance StatementFeedback inhibition by horizontal cells regulates the photoreceptor calcium channels responsible for the release of the neurotransmitter glutamate. This feedback inhibition contributes to the formation of the receptive field surrounds of early visual neurons, which is important for contrast sensitivity and color opponency in vision. The cellular mechanisms underlying feedback inhibition are not fully understood. One disputed mechanism for mammalian horizontal cell inhibitory output involves the vesicular release of the inhibitory neurotransmitter GABA. By selectively deleting the transporter that normally loads GABA into vesicles in horizontal cells, we show that horizontal cells lose their ability to modulate photoreceptor calcium signals. These findings implicate a role for the vesicular release of GABA in mediating inhibitory feedback.

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Section: Discussionmentioning

confidence: 99%

Targeted Deletion of Vesicular GABA Transporter from Retinal Horizontal Cells Eliminates Feedback Modulation of Photoreceptor Calcium Channels

Hirano

Boulter

et al. 2016

eNeuro

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“…However, a growing number of other connexins has been found to be expressed in limited sets of neurons, particularly in the retina. Among these, Cx50 (Gja8) has been found in axonless horizontal cells in rabbit retina (O'Brien et al, ), where it supports the most extensive coupling of any retinal network, and at a low expression level in mouse horizontal cells (Dorgau et al, ). Thus, it is not entirely surprising that we have found zebrafish Cx79.8 expressed in retinal neurons and in neurons elsewhere in the CNS.…”

Section: Discussionmentioning

confidence: 99%

“…These cells do not use Cx35/Cx36 (Deans and Paul, ), but rather several other connexins. Zebrafish horizontal cells have been found to express Cx55.5, Cx52.6 and Cx52.9 (Dermietzel et al, ; Zoidl et al, ; Klaassen et al, ) while mammalian horizontal cells use Cx57 (Hombach et al, ; Pan et al, ), a homologue of Cx52.6, and Cx50 (O'Brien et al, ; Dorgau et al, ). These connexins show much larger single channel conductances of 39–57 pS for Cx52.6, Cx55.5, and Cx57 (Dermietzel et al, ; Zoidl et al, ; Palacios‐Prado et al, ), and over 200 pS for Cx50 (Srinivas et al, ).…”

Section: Introductionmentioning

confidence: 99%

Zebrafish connexin 79.8 (Gja8a): A lens connexin used as an electrical synapse in some neurons

Yoshikawa

Vila

Segelken

et al. 2016

Developmental Neurobiology

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In the mammalian central nervous system a remarkably small number of connexins is used in electrical synapses, with the majority formed from Cx36. A larger number has been detected in teleosts, with some seeming to serve restricted roles. Here we report the discovery of a new connexin expressed in the zebrafish lens and a limited set of neurons. Zebrafish cx79.8 (gja8a), previously annotated incorrectly as cx50.5 based on a partial cDNA sequence, is a homologue of mammalian Cx50 (Gja8). We examined its expression through transgenic promoter-reporter constructs, in situ hybridization, and immunolabeling, and examined regulation of coupling in transfected HeLa cells. cx79.8 was expressed most strongly in the lens, but expression was also found in several groups of neurons in the cerebellum and related areas at the midbrain-hindbrain boundary, in cone photoreceptors, and in neurons in the retinal inner nuclear and ganglion cell layers. Labeling in the retina with antibodies against two C-terminal epitopes revealed numerous small punctate spots in the inner plexiform layer and along the somata of cones. Abundant gap junctions were labeled in the outer 1/3 of the lens, but were absent from the center, suggesting that the epitopes or the entire protein was absent from the center. Cx79.8 tracer coupling was strongly regulated by phosphorylation, and was extremely low in control conditions in HeLa cells due to protein phosphatase 2A activity. These properties allow coupling to be strongly restricted in situ, a frequently observed property for electrical synapses.

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“…They form GJs of both the primary and secondary rod pathways (Feigenspan et al, 2001, 2004; Güldenagel et al, 2001; Mills et al, 2001; Deans et al, 2002; Lee et al, 2003; Han and Massey, 2005; Lin et al, 2005; Maxeiner et al, 2005) and also ganglion-to-ganglion (GC-to-GC) and ganglion-to-amacrine cell (GC-to-AC) GJs (Hidaka et al, 2004; Schubert et al, 2005a,b; Völgyi et al, 2005, 2009, 2013a,b). In contrast, the high permeable Cx50 and Cx57 GJs connect horizontal cells to maintain an outer retinal syncytium (Hombach et al, 2004; Janssen-Bienhold et al, 2009; Dorgau et al, 2015; Bolte et al, 2016). While functions that GJs play in the retina seem conservative across vertebrate species (Völgyi et al, 2013a), the core of our knowledge stems from only a handful of popular species including the mouse, rat, rabbit, and monkey.…”

Section: Introductionmentioning

confidence: 99%

Connexin36 Expression in the Mammalian Retina: A Multiple-Species Comparison

Kovács-Öller

Debertin

Balogh

et al. 2017

Front. Cell. Neurosci.

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Much knowledge about interconnection of human retinal neurons is inferred from results on animal models. Likewise, there is a lack of information on human retinal electrical synapses/gap junctions (GJ). Connexin36 (Cx36) forms GJs in both the inner and outer plexiform layers (IPL and OPL) in most species including humans. However, a comparison of Cx36 GJ distribution in retinas of humans and popular animal models has not been presented. To this end a multiple-species comparison was performed in retinas of 12 mammals including humans to survey the Cx36 distribution. Areas of retinal specializations were avoided (e.g., fovea, visual streak, area centralis), thus observed Cx36 distribution differences were not attributed to these species-specific architecture of central retinal areas. Cx36 was expressed in both synaptic layers in all examined retinas. Cx36 plaques displayed an inhomogenous IPL distribution favoring the ON sublamina, however, this feature was more pronounced in the human, swine and guinea pig while it was less obvious in the rabbit, squirrel monkey, and ferret retinas. In contrast to the relative conservative Cx36 distribution in the IPL, the labels in the OPL varied considerably among mammals. In general, OPL plaques were rare and rather small in rod dominant carnivores and rodents, whereas the human and the cone rich guinea pig retinas displayed robust Cx36 labels. This survey presented that the human retina displayed two characteristic features, a pronounced ON dominance of Cx36 plaques in the IPL and prevalent Cx36 plaque conglomerates in the OPL. While many species showed either of these features, only the guinea pig retina shared both. The observed similarities and subtle differences in Cx36 plaque distribution across mammals do not correspond to evolutionary distances but may reflect accomodation to lifestyles of examined species.

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Connexin50 couples axon terminals of mouse horizontal cells by homotypic gap junctions

Cited by 22 publications

References 51 publications

Targeted Deletion of Vesicular GABA Transporter from Retinal Horizontal Cells Eliminates Feedback Modulation of Photoreceptor Calcium Channels

Targeted Deletion of Vesicular GABA Transporter from Retinal Horizontal Cells Eliminates Feedback Modulation of Photoreceptor Calcium Channels

Zebrafish connexin 79.8 (Gja8a): A lens connexin used as an electrical synapse in some neurons

Connexin36 Expression in the Mammalian Retina: A Multiple-Species Comparison

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