Our work focuses on several different synapses and cell types in the inner retina. We have expanded our study of inhibitory synaptic connections made by amacrine cells within the inner retina, to understand how feedforward and feedback inhibition contributes to signal processing in this network. We find that A17 amacrine cells provide rapid GABAergic feedback to rod bipolar cell terminals via a release process that is independent of membrane depolarization or voltage-gated calcium channels (Chavez, et al., 2006). This rapid feedback, driven by activation of calcium-permeable AMPA receptors in the A17 amacrine cell, may be essential to prevent the rapid depletion of readily-releasable vesicles from the rod bipolar cell synaptic terminal (Singer and Diamond, 2006). More recent work (Chavez and Diamond, 2008;Chavez, et al., 2010) indicate that two other types of feedback inhibition onto bipolar cells exhibit different characteristics and mechanisms of modulation. In addition to providing valuable information about feedback, this work is enabling us to begin to make functional sense of the vast array of amacrine cells (>two dozen cell types) in the mammalian retina. We have combined electrophysiological and imaging techniques to explore the mechanisms of signal integration in A17 amacrine cells and have found that active, calcium-dependent conductances may be essential to compartmentalize signal processing within A17 dendrites (Grimes, et al., 2010). Currently we are studying how the biophysical properties of this synapse changes with different phases of the circadian cycle. We also have combined recordings from synaptically connected cell pairs with light-evoked responses from rod bipolar cells and AII amacrine cells to study how this important synapse in the rod pathway transmits visual information. We find that this synapse response to changes in luminance with a biphasic response. The slow, sustained component of the response encodes absolute luminance, and the transient component encodes Weber contrast (Oesch and Diamond, 2011). Recordings from synaptically coupled rod bipolar and AII amacrine cells showed that Weber contrast is computed via careful regulation of the readily releasable pool of synaptic vesicles. Future experiments are aimed at determining how synaptic inhibition influences this computation. In addition, we are combining electrophysiology, imaging approaches and cellular/network modeling to explore dendritic integration in directionally-selective ganglion cells.

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Graydon, Cole W; Lieberman, Evan E; Rho, Nao et al. (2018) Synaptic Transfer between Rod and Cone Pathways Mediated by AII Amacrine Cells in the Mouse Retina. Curr Biol 28:2739-2751.e3
Wang, Xu; Zhao, Lian; Zhang, Jun et al. (2016) Requirement for Microglia for the Maintenance of Synaptic Function and Integrity in the Mature Retina. J Neurosci 36:2827-42
Zhang, Jun; Petralia, Ronald S; Wang, Ya-Xian et al. (2016) High-Resolution Quantitative Immunogold Analysis of Membrane Receptors at Retinal Ribbon Synapses. J Vis Exp :53547
Sluch, Valentin M; Davis, Chung-ha O; Ranganathan, Vinod et al. (2015) Differentiation of human ESCs to retinal ganglion cells using a CRISPR engineered reporter cell line. Sci Rep 5:16595
Poleg-Polsky, Alon (2015) Effects of Neural Morphology and Input Distribution on Synaptic Processing by Global and Focal NMDA-Spikes. PLoS One 10:e0140254
Grimes, William N; Zhang, Jun; Tian, Hua et al. (2015) Complex inhibitory microcircuitry regulates retinal signaling near visual threshold. J Neurophysiol 114:341-53
Bemben, Michael A; Shipman, Seth L; Hirai, Takaaki et al. (2014) CaMKII phosphorylation of neuroligin-1 regulates excitatory synapses. Nat Neurosci 17:56-64
Graydon, Cole W; Zhang, Jun; Oesch, Nicholas W et al. (2014) Passive diffusion as a mechanism underlying ribbon synapse vesicle release and resupply. J Neurosci 34:8948-62
Diamond, Jeffrey S; Lukasiewicz, Peter D (2012) Amacrine cells: seeing the forest and the trees. Vis Neurosci 29:1-2
Oesch, Nicholas W; Diamond, Jeffrey S (2011) Ribbon synapses compute temporal contrast and encode luminance in retinal rod bipolar cells. Nat Neurosci 14:1555-61

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