In this competing renewal application, we propose to continue and extend our investigations on rod and cone signaling pathways at the bipolar cell (BC), amacrine cell (AC) and ganglion cell (GC) levels in the dark-adapted mouse retina. We will focus our efforts to study the BC and AC synaptic circuitries mediating rod, M-cone and M/S-cone signal transmission to three types of alpha ganglion cells (alphaGCs), and to determine how glycinergic and GABAergic ACs regulate light-evoked signals in alphaGCs via the AC cone BC GC feedback pathways and the AC GC feedforward synapses. There are three specific aims: (1) to correlate physiological BC types with anatomical BC types in the three alphaGC circuitries and to identify possible synaptic contacts between rods/cones and BCs and between BCs and alphaGCs;(2) to determine the relative strengths of rod- and cone-mediated inputs to BCs and alphaGCs and mechanisms of signal integration in the 3 alphaGC circuitries by analyzing BCs'and alphaGCs'light-evoked cation currents ( IC) in wildtype, Tralpha-/- and Gnat2cplf3 mice;and (3) to determine relative glycinergic and GABAergic AC contributions to alphaGCs'light-evoked inhibitory and BC synaptic inputs and possible synaptic connectivity between individual GABAergic ACs and alphaGCs by double label and dual voltage clamp techniques. The goal of our research is to understand how mammalian retinal networks process visual images, a basic research priority of the NEI, and to provide crucial information on how individual retinal neurons and synapses dysfunction in disease states, such as congenital stationary night blindness and glaucoma, a translational research priority of the NEI. Moreover, knowledge of specific mammalian retinal circuitries in healthy and diseased eyes will be useful for developing new gene/drug therapies for retinal disorders, such as retinitis pigmentosa and glaucoma, as well as for designing effective retinal prosthetic devices.

Public Health Relevance

The goal of our research is to understand how the mammalian retinal network processes visual information, and how individual retinal neurons and synapses dysfunction in eye diseases, such as retinitis pigmentosa, congenital stationary night blindness and glaucoma. Results obtained will provide a crucial knowledge base for developing new gene/drug therapies against retinal disorders and effective retinal prosthetic devices.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Greenwell, Thomas
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Baylor College of Medicine
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Tse, Dennis Y; Chung, Inyoung; Wu, Samuel M (2014) Possible roles of glutamate transporter EAAT5 in mouse cone depolarizing bipolar cell light responses. Vision Res 103:63-74
Tse, Dennis Y; Chung, Inyoung; Wu, Samuel M (2014) Pharmacological inhibitions of glutamate transporters EAAT1 and EAAT2 compromise glutamate transport in photoreceptor to ON-bipolar cell synapses. Vision Res 103:49-62
Pang, Ji-Jie; Paul, David L; Wu, Samuel M (2013) Survey on amacrine cells coupling to retrograde-identified ganglion cells in the mouse retina. Invest Ophthalmol Vis Sci 54:5151-62
Frankfort, Benjamin J; Khan, A Kareem; Tse, Dennis Y et al. (2013) Elevated intraocular pressure causes inner retinal dysfunction before cell loss in a mouse model of experimental glaucoma. Invest Ophthalmol Vis Sci 54:762-70
Gao, Fan; Pang, Ji-Jie; Wu, Samuel M (2013) Sign-preserving and sign-inverting synaptic interactions between rod and cone photoreceptors in the dark-adapted retina. J Physiol 591:5711-26
Pang, Ji-Jie; Gao, Fan; Paul, David L et al. (2012) Rod, M-cone and M/S-cone inputs to hyperpolarizing bipolar cells in the mouse retina. J Physiol 590:845-54
Pang, Ji-Jie; Gao, Fan; Wu, Samuel M (2012) Physiological characterization and functional heterogeneity of narrow-field mammalian amacrine cells. J Physiol 590:223-34
Price, Brandee A; Sandoval, Ivette M; Chan, Fung et al. (2011) Mislocalization and degradation of human P23H-rhodopsin-GFP in a knockin mouse model of retinitis pigmentosa. Invest Ophthalmol Vis Sci 52:9728-36
Cai, Zhigang; Simons, David L; Fu, Xin-Yuan et al. (2011) Loss of Shp2-mediated mitogen-activated protein kinase signaling in Muller glial cells results in retinal degeneration. Mol Cell Biol 31:2973-83
Pang, Ji-Jie; Wu, Samuel M (2011) Morphology and immunoreactivity of retrogradely double-labeled ganglion cells in the mouse retina. Invest Ophthalmol Vis Sci 52:4886-96

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