Electrical synaptic transmission via gap junctions (gjs) is an important mode of neuronal communication in the CNS. An elegant example is the retina in which each of the five main neuronal types is electrically coupled via gjs. The broad distribution, structure, and regulation of retinal gjs suggest a diversity of functional roles in vsual processing;elucidating these roles forms the long-term goal of our experimental program. Here we propose to study the gjs in the inner mouse retina, which subserve a rich and complex variety of electrical circuits.
The first aim of this proposal is to determine the role of gjs in creating the robust, correlated activity displayed by ganglion cells. Correlated ganglion cell activity is believed to have a number of functions, including enhancement of signal saliency and encoding of specific information about visual stimuli such as intensity, size, and motion. It is presently unclear whether concerted ganglion cell activity reflects common excitatory inputs via chemical synapses and/or gj-mediated electrical coupling between ganglion cells and their neighbors. We propose a multidisciplinary approach combining electrophysiological, pharmacological, and optogenetic techniques applied to transgenic and knockout mouse lines to differentiate the circuits responsible for correlated ganglion cell activity.
The second aim will focus on concerted activity of ganglion cells separated over long distances and its role in encoding global visual information pertinent to perceptual grouping and object recognition. We will test the hypothesis that such """"""""long-range"""""""" concerted activity is generated by wide-field amacrine cells that form gjs with ganglion cells separated by at least 750 ?m. We will test whether deletion of gjs between ganglion and amacrine cells abolishes the concerted activity evokes by contiguous stimuli thereby producing a behavioral dysfunction rendering animals less capable of discriminating large, contiguous objects from two discrete objects. In the third aim we will study the novel idea the ganglion cells can alter intraretinal activity by signaling back to amacrine cells through interconnecting gjs. We posit that ganglion cells can alter the activity of coupled amacrine cell neighbors, which, in turn, inhibit other ganglion cells via conventional chemical synapses. This form of intraretinal signaling by ganglion cells creates a circuit providing a novel form of lateral inhibition. In the final aim, we propose to combine labeling with the gj-permeant dyes Po-, Pro-1, and Neurobiotin to provide a complete description of the different gj-mediated electrical circuits in the inner mouse retina that help produce the responses of the >20 different ganglion cell subtypes, which are transmitted to the brain. Deficits in gj communication have been implicated in a number of brain neuropathies, including visual impairments associated with retinitis pigmentosa, glaucoma and ischemic retinopathy. The experimental program proposed here will extend our understanding of the distribution and physiological roles of gjs, which form important prerequisites for determining how gj dysfunction affects neural function so as to suggest novel targets for the treatment for human disease.

Public Health Relevance

As the most important sense in humans, vision is the modality through which we interact mainly with the world around us. Gap junction dysfunction has been associated with a number of neurological defects related to vision, including retinitis pigmentosa, ischemic retinopathy, and glaucoma. The experimental program proposed here will extend our understanding of the distribution and physiological roles of gap junctions, which is fundamental to understanding how gap junction dysfunction affects retinal activity, so as to suggest novel treatments for human disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Greenwell, Thomas
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State College of Optometry
Schools of Optometry/Ophthalmol
New York
United States
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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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