My long-term goal is to understand the biological basis of visual processing at the level of neural circuits and synapses. I am pursuing this goal in the mammalian retina, a tissue comprised of ~70 cell types: ~3-4 photoreceptors (depending on species), ~50 interneurons (horizontal, bipolar and amacrine cells) and ~20 output neurons (ganglion cells). Over the past period, we focused on two types of ganglion cell (ON and OFF Alpha cell) and elucidated fundamental components of their synaptic inputs and mechanisms for contrast adaptation. These accomplishments allow us to now expand our studies to a dozen types of ganglion cell that we recognize based on a combination of functional properties (light-evoked synaptic conductance) and structural properties (dendritic tree diameter and stratification level in the inner plexiform layer).
Aim 1 will reveal fundamental circuit mechanisms for night vision, by determining how rod signals are transmitted, via an identified neural pathway, to each ganglion cell type. Rods synapse with rod bipolar cells, which in turn excite the AII amacrine cell;the AII cell signals directly certain ganglion cell types and indirectly others by synapsing with the presynaptic cone bipolar terminal. Preliminary data suggest that a small group of OFF ganglion cell types receives direct AII cell synapses;another group receives indirect synapses, whereas a third group lacks connection to the circuit and loses function in dim light. To encode visual signals in daylight, each ganglion cell type receives glutamatergic synapses from one or more types of cone bipolar cell, but we need to test which ganglion cell types encode glutamate release with an NMDA receptor (Aim 2). Compared to the other major type, AMPA receptors, NMDA receptors have a conductance that is voltage-dependent, lacks desensitization and has relatively slow kinetics. We want to understand the role of NMDA receptors in visual processing, and as a first step we will identify which ganglion cell types express them. For each type, we will test for functional expression by applying NMDA directly;we will test further whether these receptors contribute to high contrast responses under normal physiological conditions. Finally, we will test quantitatively the role of NMDA receptors in visual processing (Aim 3). We will model ligand-gated receptor contributions to contrast responses and test whether NMDA receptors are used preferentially for encoding low versus high contrast. We will test further whether the slow kinetics of the NMDA receptor-mediated response encodes preferentially low temporal frequencies. Proposed studies will yield basic understanding of how retinal circuits and synapses process information and provide background for understanding retinal diseases that either compromise the rod pathway or involve NMDA receptor-mediated excitotoxicity.

Public Health Relevance

Proposed studies will provide background for understanding the impact of eye diseases that impair night vision (i.e., retinitis pigmentosa, congenital stationary night blindness) and eye diseases that involve cell death caused by excitotoxicity (i.e., glaucoma, ischemia). Studies will lead to a better understanding of how the retina processes visual information, which could facilitate the development of prosthetic devices for stimulating preserved retinal cells in certain forms of blindness.

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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Yale University
Schools of Medicine
New Haven
United States
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Park, Silvia J H; Kim, In-Jung; Looger, Loren L et al. (2014) Excitatory synaptic inputs to mouse on-off direction-selective retinal ganglion cells lack direction tuning. J Neurosci 34:3976-81
Borghuis, Bart G; Looger, Loren L; Tomita, Susumu et al. (2014) Kainate receptors mediate signaling in both transient and sustained OFF bipolar cell pathways in mouse retina. J Neurosci 34:6128-39
Stafford, Benjamin K; Park, Silvia J H; Wong, Kwoon Y et al. (2014) Developmental changes in NMDA receptor subunit composition at ON and OFF bipolar cell synapses onto direction-selective retinal ganglion cells. J Neurosci 34:1942-8
Ke, Jiang-Bin; Wang, Yanbin V; Borghuis, Bart G et al. (2014) Adaptation to background light enables contrast coding at rod bipolar cell synapses. Neuron 81:388-401
Stafford, Benjamin K; Manookin, Michael B; Singer, Joshua H et al. (2014) NMDA and AMPA receptors contribute similarly to temporal processing in mammalian retinal ganglion cells. J Physiol 592:4877-89
Marvin, Jonathan S; Borghuis, Bart G; Tian, Lin et al. (2013) An optimized fluorescent probe for visualizing glutamate neurotransmission. Nat Methods 10:162-70
Beier, Kevin T; Borghuis, Bart G; El-Danaf, Rana N et al. (2013) Transsynaptic tracing with vesicular stomatitis virus reveals novel retinal circuitry. J Neurosci 33:35-51
Borghuis, Bart G; Marvin, Jonathan S; Looger, Loren L et al. (2013) Two-photon imaging of nonlinear glutamate release dynamics at bipolar cell synapses in the mouse retina. J Neurosci 33:10972-85
Demb, Jonathan B; Singer, Joshua H (2012) Intrinsic properties and functional circuitry of the AII amacrine cell. Vis Neurosci 29:51-60
Weick, Michael; Demb, Jonathan B (2011) Delayed-rectifier K channels contribute to contrast adaptation in mammalian retinal ganglion cells. Neuron 71:166-79

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