Work over the last decade indicates that electrical synaptic transmission via gap junctions forms an important mode of neuronal communication in the retina. It is now clear that gap junctions are ubiquitous in the retina, being expressed by each of the five major cell classes. In addition, retinal gap junctions have been shown to be dynamically regulated by changes in ambient illumination and circadian rhythms acting through light-activated neuromodulators such as dopamine and nitric oxide. These data suggest that gap junctions play an important role in light adaptation. The long-term goal of our research is define the distribution and function of gap junctions in the mammalian retina so as to define their roles in the processing of visual signals.
One specific aim of this proposal is to examine the role of gap junctions in the transmission of rod-mediated signals. Experiments are proposed to study the role of coupling between AII amacrine cells in maintaining the fidelity of the most sensitive rod signals and the role of rod-cone coupling in delivering rod-mediated signals to the horizontal cells.
A second aim i s to study masked synaptic inputs to retinal neurons, delivered by circuits that utilize gap junctions. Our recent data indicate that rod-mediated synaptic signals to some ganglion cell subtypes are masked in that they are not translated into a spike code and sent to the brain. A second masked input that will be studied is an OFF response in ON direction selective ganglion cells that is delivered by gap junctions made with a subtype of polyaxonal amacrine cells and is normally hidden by inhibitory circuitry. We will determine if masked synaptic inputs in the retina reflect normal dynamics in visual signaling with changing stimulus conditions or a strategy for economic wiring of the retina.
A third aim i s to study the role of starburst amacrine cell Kv3 potassium channels in generating direction selective responses, a computation whose mechanism has become a classic question in retinal neurobiology.
A final aim i s to define the structure and function of the 20-30 subtypes of amacrine cells in the mammalian retina to elucidate their roles in generating the output signals of the retina carried by the postsynaptic ganglion cells to the brain. The proposed experiments center on electrophysiological recording of the responses of retinal neurons and their labeling with the gap-permeant biotinylated tracers. The function of gap junctions will be assessed by selectively ablating them either pharmacologically or by knocking out specific connexin proteins in mutant mouse models. Gap junctions have been implicated in a number of neurological diseases including X- linked Charcot-Marie-Tooth disease, nonsyndromic autosomal deafness and neuroprotection following stroke or trauma. Although focused on the function and regulation of gap junctions in mammalian retina, the proposed work will nevertheless provide important insights into the roles of electrical synaptic transmission throughout the brain.

Public Health Relevance

As the most important sense in humans, vision is the modality through which we interact mainly with the world around us. This proposal will examine the role of gap junctions in the retina, which are modulated by light and are thereby likely to play a key role in light adaptation. Gap junctions have been implicated in a number of neurological defects including X-linked Charcot-Marie-Tooth disease, nonsyndromic autosomal deafness and neuroprotection and may play a role in retinopathies related to adaptation and vision under dim ambient light conditions.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Greenwell, Thomas
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New York University
Schools of Medicine
New York
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Slavi, Nefeli; Toychiev, Abduqodir H; Kosmidis, Stylianos et al. (2018) Suppression of connexin 43 phosphorylation promotes astrocyte survival and vascular regeneration in proliferative retinopathy. Proc Natl Acad Sci U S A 115:E5934-E5943
Roy, Kaushambi; Kumar, Sandeep; Bloomfield, Stewart A (2017) Gap junctional coupling between retinal amacrine and ganglion cells underlies coherent activity integral to global object perception. Proc Natl Acad Sci U S A 114:E10484-E10493
Akopian, Abram; Kumar, Sandeep; Ramakrishnan, Hariharasubramanian et al. (2017) Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma. J Clin Invest 127:2647-2661
Pan, Feng; Toychiev, Abduqodir; Zhang, Yi et al. (2016) Inhibitory masking controls the threshold sensitivity of retinal ganglion cells. J Physiol 594:6679-6699
Akopian, Abram; Atlasz, Tamas; Pan, Feng et al. (2014) Gap junction-mediated death of retinal neurons is connexin and insult specific: a potential target for neuroprotection. J Neurosci 34:10582-91
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
Farajian, Reza; Pan, Feng; Akopian, Abram et al. (2011) Masked excitatory crosstalk between the ON and OFF visual pathways in the mammalian retina. J Physiol 589:4473-89
Osterhout, Jessica A; Josten, Nicko; Yamada, Jena et al. (2011) Cadherin-6 mediates axon-target matching in a non-image-forming visual circuit. Neuron 71:632-9
Hu, Edward H; Pan, Feng; Völgyi, Béla et al. (2010) Light increases the gap junctional coupling of retinal ganglion cells. J Physiol 588:4145-63
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

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