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

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          Abstract

          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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          Most cited references53

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          The diverse functional roles and regulation of neuronal gap junctions in the retina.

          Electrical synaptic transmission through gap junctions underlies direct and rapid neuronal communication in the CNS. The diversity of functional roles that electrical synapses have is perhaps best exemplified in the vertebrate retina, in which gap junctions are formed by each of the five major neuron types. These junctions are dynamically regulated by ambient illumination and by circadian rhythms acting through light-activated neuromodulators such as dopamine and nitric oxide, which in turn activate intracellular signalling pathways in the retina.The networks formed by electrically coupled neurons are plastic and reconfigurable, and those in the retina are positioned to play key and diverse parts in the transmission and processing of visual information at every retinal level.
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            Connexin36 is essential for transmission of rod-mediated visual signals in the mammalian retina.

            To examine the functions of electrical synapses in the transmission of signals from rod photoreceptors to ganglion cells, we generated connexin36 knockout mice. Reporter expression indicated that connexin36 was present in multiple retinal neurons including rod photoreceptors, cone bipolar cells, and AII amacrine cells. Disruption of electrical synapses between adjacent AIIs and between AIIs and ON cone bipolars was demonstrated by intracellular injection of Neurobiotin. In addition, extracellular recording in the knockout revealed the complete elimination of rod-mediated, on-center responses at the ganglion cell level. These data represent direct proof that electrical synapses are critical for the propagation of rod signals across the mammalian retina, and they demonstrate the existence of multiple rod pathways, each of which is dependent on electrical synapses.
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              Tracer coupling patterns of the ganglion cell subtypes in the mouse retina.

              It is now clear that electrical coupling via gap junctions is prevalent across the retina, expressed by each of the five main neuronal types. With the introduction of mutants in which selective gap junction connexins are deleted, the mouse has recently become an important model for studying the function of coupling between retinal neurons. In this study we examined the tracer-coupling pattern of ganglion cells by injecting them with the gap junction-permanent tracer Neurobiotin to provide, for the first time, a comprehensive survey of ganglion cell coupling in the wildtype mouse retina. Murine ganglion cells were differentiated into 22 morphologically distinct subtypes based on soma-dendritic parameters. Most (16/22) ganglion cell subtypes were tracer-coupled to neighboring ganglion and/or amacrine cells. The amacrine cells coupled to ganglion cells displayed either polyaxonal or wide-field morphologies with extensive arbors. We found that different subtypes of ganglion cells were never coupled to one another, indicating that they subserved independent electrical networks. Finally, we found that the tracer-coupling patterns of the 22 ganglion cell populations were largely stereotypic across the 71 retinas studied. Our results indicate that electrical coupling is extensive in the inner retina of the mouse, suggesting 0
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                09 March 2017
                2017
                : 11
                : 65
                Affiliations
                [1] 1Department of Experimental Zoology and Neurobiology, University of Pécs Pécs, Hungary
                [2] 2János Szentágothai Research Center Pécs, Hungary
                [3] 3Retinal Electrical Synapses Research Group, Hungarian Academy of Sciences (MTA-PTE NAP B) Pécs, Hungary
                [4] 4Department of Biophysics, University of Pécs Pécs, Hungary
                [5] 5High-Field Terahertz Research Group, Hungarian Academy of Sciences (MTA-PTE) Pécs, Hungary
                [6] 6Nuclear-Mitochondrial Interactions Research Group, Hungarian Academy of Sciences (MTA-PTE) Pécs, Hungary
                [7] 7National Research Institute for Radiobiology and Radiohygiene Budapest, Hungary
                [8] 8Department of Anatomy, Histology and Embryology, Semmelweis University Budapest, Hungary
                [9] 9Department of Neuroanatomy, Institute for Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg Freiburg, Germany
                [10] 10Department of Ophthalmology, New York University Langone Medical Center, New York NY, USA
                Author notes

                Edited by: Botir T. Sagdullaev, Weill Cornell Medical College, USA

                Reviewed by: Michel Joseph Roux, Institute of Genetics and Molecular and Cellular Biology, France; Peter Lukasiewcz, Washington University School of Medicine, USA

                *Correspondence: Béla Völgyi, volgyi01@ 123456gamma.ttk.pte.hu
                Article
                10.3389/fncel.2017.00065
                5343066
                a27cc76d-88f8-41ab-af06-1cd8e5a02007
                Copyright © 2017 Kovács-Öller, Debertin, Balogh, Ganczer, Orbán, Nyitrai, Balogh, Kántor and Völgyi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 24 November 2016
                : 23 February 2017
                Page count
                Figures: 8, Tables: 0, Equations: 0, References: 55, Pages: 15, Words: 0
                Categories
                Neuroscience
                Original Research

                Neurosciences
                electrical synapses,gap junction,connexin36
                Neurosciences
                electrical synapses, gap junction, connexin36

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