Like in other brain areas, the major mode of cell to cell communication is carried out via chemically mediated synaptic signal transmission in the mammalian retina. However, this classical view has dramatically changed over the last decade as converging evidence indicates that electrical synapses via gap junctions form a second and significant mode of interneuronal communication. Gap junctions are ubiquitous in the retina, displayed by all five major classes of retinal neurons. Retinal gap junctions also play a variety of roles including signal transmission, improving signal/noise ratio and synchronization of neuronal activity. Moreover, it has been shown that retinal gap junctions are dynamically regulated by changes in ambient light levels and by circadian rhythms. Therefore, direct intercellular communication via electrical synapses must play a key role in the intraretinal propagation and integration of signals that are ultimately transmitted to the brain via the output ganglion cells (GCs). The goal of the proposed research is to study the distribution, molecular makeup, function and regulation of gap junctions formed by GCs in the mouse retina. Accordingly, my specific aims are: (1) to examine the distribution of GC gap junctions in the mouse retina;(2) to study the connexin subunit composition of these gap junctions;(3) to elucidate the role of different GC gap junctions;(4) to study the effects of dark/light adaptation on the physiology of GC gap junctions;(5) to study the pharmacology of GC gap junctions. In this project I will use a multidisciplinary approach, including morphology, immunocytochemistry, electrophysiology, pharmacology and usage of transgenic mouse strains to study these above points. I anticipate that this project will significantly contribute to our understanding about how visual signals are generated and how the retina works. The relevance of this study is strongly justified by the fact that malfunction of gap junctions are associated with neurological diseases including X- linked Charcot-Marie-Tooth disease and nonsyndromic hearing loss as well as with an abnormally extensive posttraumatic cell loss. Therefore, it is likely that defects in retinal gap junctions will lead to retinopathies associated with impairment of signaling and adaptation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017832-05
Application #
8120718
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
2007-09-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$284,760
Indirect Cost
Name
New York University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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
Bloomfield, Stewart A; Völgyi, Béla (2009) The diverse functional roles and regulation of neuronal gap junctions in the retina. Nat Rev Neurosci 10:495-506
Ackert, Jessica M; Farajian, Reza; Volgyi, Bela et al. (2009) GABA blockade unmasks an OFF response in ON direction selective ganglion cells in the mammalian retina. J Physiol 587:4481-95
Völgyi, Béla; Chheda, Samir; Bloomfield, Stewart A (2009) Tracer coupling patterns of the ganglion cell subtypes in the mouse retina. J Comp Neurol 512:664-87