Light responses of photoreceptors are transmitted across the first synapse in the retina by changes in the ongoing release of glutamate-filled vesicles.
Aim 1 proposes to identify the mechanisms that limit rates of ongoing release from cones in light and dark. The rate-limiting steps in continuous release are calcium-dependent, thus linking light-evoked changes in membrane potential to release rates through voltage-dependent changes in calcium entry. Modeling, imaging, and electrophysiology will be used to test the hypothesis that the actions of calmodulin and calmodulin kinase II regulate sustained release by speeding molecular priming of synaptic vesicles or by enhancing vesicle attachment at the ribbon-style active zone. Experiments also test whether the rate of sustained release may be limited by the rate at which the functional status of release sites can be restored after a prio vesicle fusion event. One way in which prior release might restrict subsequent release site function is by disrupting the close spatial relationship between calcium channels and release sites. Unlike cones where release occurs only at ribbon-style active zones, most of the slow sustained release from rods occurs at ectopic sites outside the active zone. This ectopic, non-ribbon release is driven by release of calcium stored in the endoplasmic reticulum.
Aim 2 tests the hypothesis that sustained release of calcium from the endoplasmic reticulum drives synaptic release from rods in darkness and that this release from intracellular stores is sustained by the continuous tunneling of calcium ions through endoplasmic reticulum from perikaryon to synaptic terminal. Cones have as many as 50 ribbon-style active zones apiece.
Aim 3 asks whether calcium changes at individual ribbons in a cone differ in their voltage-dependence, thus promoting synaptic heterogeneity, or whether they operate like a single distributed ribbon. Together, these experiments are designed to identify key processes that shape vision at the first synapse in the retina and are essential for understanding the consequences of disease-related changes in synaptic activity as well as for restoring normal visual function by therapeutic interventions.

Public Health Relevance

Understanding the biophysical mechanisms of synaptic release from photoreceptors is necessary for understanding basic mechanisms of vision and the functional consequences of damage to photoreceptor synapses caused by mutations in synaptic proteins or diseases such as macular degeneration and ischemia. Understanding these mechanisms is also needed for designing therapies to restore normal retinal function to diseased eyes using retinal stem cells, optogenetics or 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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University of Nebraska Medical Center
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Wen, Xiangyi; Van Hook, Matthew J; Grassmeyer, Justin J et al. (2018) Endocytosis sustains release at photoreceptor ribbon synapses by restoring fusion competence. J Gen Physiol 150:591-611
Grassmeyer, Justin J; Thoreson, Wallace B (2017) Synaptic Ribbon Active Zones in Cone Photoreceptors Operate Independently from One Another. Front Cell Neurosci 11:198
Van Hook, Matthew J; Babai, Norbert; Zurawski, Zack et al. (2017) A Presynaptic Group III mGluR Recruits G??/SNARE Interactions to Inhibit Synaptic Transmission by Cone Photoreceptors in the Vertebrate Retina. J Neurosci 37:4618-4634
Datta, Proleta; Gilliam, Jared; Thoreson, Wallace B et al. (2017) Two Pools of Vesicles Associated with Synaptic Ribbons Are Molecularly Prepared for Release. Biophys J 113:2281-2298
Warren, Ted J; Van Hook, Matthew J; Tranchina, Daniel et al. (2016) Kinetics of Inhibitory Feedback from Horizontal Cells to Photoreceptors: Implications for an Ephaptic Mechanism. J Neurosci 36:10075-88
Warren, Ted J; Van Hook, Matthew J; Supuran, Claudiu T et al. (2016) Sources of protons and a role for bicarbonate in inhibitory feedback from horizontal cells to cones in Ambystoma tigrinum retina. J Physiol 594:6661-6677
Cork, Karlene M; Van Hook, Matthew J; Thoreson, Wallace B (2016) Mechanisms, pools, and sites of spontaneous vesicle release at synapses of rod and cone photoreceptors. Eur J Neurosci 44:2015-27
Thoreson, Wallace B; Van Hook, Matthew J; Parmelee, Caitlyn et al. (2016) Modeling and measurement of vesicle pools at the cone ribbon synapse: Changes in release probability are solely responsible for voltage-dependent changes in release. Synapse 70:1-14
Grishchuk, Yulia; Stember, Katherine G; Matsunaga, Aya et al. (2016) Retinal Dystrophy and Optic Nerve Pathology in the Mouse Model of Mucolipidosis IV. Am J Pathol 186:199-209
Chen, Minghui; Van Hook, Matthew J; Thoreson, Wallace B (2015) Ca2+ Diffusion through Endoplasmic Reticulum Supports Elevated Intraterminal Ca2+ Levels Needed to Sustain Synaptic Release from Rods in Darkness. J Neurosci 35:11364-73

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