A compelling body of evidence indicates that signals from rod photoreceptors use multiple pathways to reach ganglion cells. In the canonical primary pathway, rod signals gain access to downstream cone circuitry through the AII amacrines which form electrical synapses (gap junctions) with ON cone bipolar and glycinergic synapses with OFF cone bipolar. In the secondary pathway, electrical synapses between rods and cones provide a direct entry for rod signals into cone circuits. However, a credible direct demonstration of rod-cone coupling has been made only in monkey. Because technical issues prevent a conventional approach to measurement of rod-cone coupling in the mouse (i.e. injections of junction-permeant tracers using microelectrodes), we developed a novel method to evaluated coupling. The method is based on transgenic, cell-specific expression of a transporter, the movement of the transported molecule through gap junctions to neighboring cells and the detection of that molecule with specific antibodies. This method eliminates the need for any physical manipulation of the live cells. Despite the widely held assumption that rod-cone coupling underlies the secondary pathway, we found no evidence of rod-cone coupling in the mouse. Thus, we propose a set of experiments to determine the generality of the canonical secondary pathway model by testing rod-cone coupling in the rabbit and to evaluate cone-cone and possible rod-rod coupling in mouse and rabbit retinas. In contrast, our data strongly support the basic tenets of the rod primary pathway. However, while the prevailing model postulates that AII amacrines express Cx36 and cone ON bipolar express Cx45, forming a 'heterotypic'electrical synapse, our data indicate more complexity. We propose there are two types of glycinergic amacrine cells, those expressing Cx45 and those expressing Cx36 and that each forms homotypic junctions with a subset of cone bipolar cells expressing the same connexin. We hypothesize that the expression of incompatible connexins is mechanism to allow segregation of amacrine- cone bipolar interactions according to cell subtype. We will determine the types of cone bipolar involved in rod primary pathway signaling and which connexins they employ. In addition, we will determine if different retinal connexins can functionally interact.

Public Health Relevance

Our studies address fundamental questions about the neural circuitry employed by rod photoreceptors, which contribute to retinal responses over a range of light inputs from near total darkness to bright moonlight. Disorders of the neural retina are a primary cause of human blindness and a rational pursuit of therapeutic strategies requires a full understand of mammalian retinal circuitry.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY014127-05A1
Application #
8038927
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
2002-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$422,500
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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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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