In the retina, gap junctions are established by many cell types and may participate in retinal circuitry in a variety of ways. Gap junctions are composed of connexins, encoded by a >20-member family of highly related genes. Only one of these, connexin36 (Cx36), has been conclusively demonstrated in retinal neurons. Using a Cx36 knockout (KO) mouse incorporating a histochemical reporter, we found Cx36 to be present in most or all All amacrine cells, many photoreceptors, subsets of ON and OFF cone bipolar cells and a low number of ganglion cells. However, horizontal cells and many ganglion cells establish gap junctions yet do not express Cx36. Using RT-PCR, we have found Cx45 and Cx57 to be prominently expressed in mouse retina. We propose to characterize the cellular distribution of these connexins and determine if other gap junction channel-forming proteins may be present in retinal neurons. Many lines of evidence indicate that rod photoreceptor signals utilize multiple pathways to reach ganglion cells. In our Cx36 KO, ON ganglion cell responses to scotopic stimuli are completely eliminated, indicating that Cx36 is required in all pathways contributing to rod ON signaling. We showed that gap junctional coupling between AII and cone ON bipolar cells, the presumed 'primary' pathway for rod photoreceptor signaling, was abolished in the KO. Since a proposed 'alternative' pathway involved gap junction between rods and cones, and since we found Cx36 expression in photoreceptors, our findings were consistent with the proposed 'alternative' pathway. However, recent studies of retinas from mice genetically altered to lack cones suggest that rod-cone coupling does not contribute to rod photoreceptor signaling. In addition, it has not been technically feasible to measure junctional coupling between photoreceptors in mouse retinas. Therefore, to resolve the discrepancy between current models of the 'alternative' pathway, we will 1) develop a method to directly assess rod-cone coupling in WT and Cx36 KO mice and 2) produce conditional knockouts that eliminate Cx36 specifically from either cones or from AII amacrine cells. Then, ganglion cell responses to light can be assessed in retinas where either primary or alternative pathways are ablated.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Mariani, Andrew P
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Harvard University
Schools of Medicine
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Rodriguez, Allen R; de Sevilla Müller, Luis Pérez; Brecha, Nicholas C (2014) The RNA binding protein RBPMS is a selective marker of ganglion cells in the mammalian retina. J Comp Neurol 522:1411-43
Völgyi, Béla; Pan, Feng; Paul, David L et al. (2013) Gap junctions are essential for generating the correlated spike activity of neighboring retinal ganglion cells. PLoS One 8:e69426
Hou, Mingli; Li, Yaqiao; Paul, David L (2013) A novel, highly sensitive method for assessing gap junctional coupling. J Neurosci Methods 220:18-23
Gire, David H; Franks, Kevin M; Zak, Joseph D et al. (2012) Mitral cells in the olfactory bulb are mainly excited through a multistep signaling path. J Neurosci 32:2964-75
Pang, Ji-Jie; Gao, Fan; Paul, David L et al. (2012) Rod, M-cone and M/S-cone inputs to hyperpolarizing bipolar cells in the mouse retina. J Physiol 590:845-54
Beaumont, Michael; Maccaferri, Gianmaria (2011) Is connexin36 critical for GABAergic hypersynchronization in the hippocampus? J Physiol 589:1663-80
Postma, Friso; Liu, Cheng-Hang; Dietsche, Caitlin et al. (2011) Electrical synapses formed by connexin36 regulate inhibition- and experience-dependent plasticity. Proc Natl Acad Sci U S A 108:13770-5
Brown, Timothy M; Allen, Annette E; Wynne, Jonathan et al. (2011) Visual responses in the lateral geniculate evoked by Cx36-independent rod pathways. Vision Res 51:280-7
Pan, Feng; Paul, David L; Bloomfield, Stewart A et al. (2010) Connexin36 is required for gap junctional coupling of most ganglion cell subtypes in the mouse retina. J Comp Neurol 518:911-27
Pang, Ji-Jie; Gao, Fan; Lem, Janis et al. (2010) Direct rod input to cone BCs and direct cone input to rod BCs challenge the traditional view of mammalian BC circuitry. Proc Natl Acad Sci U S A 107:395-400

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