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)
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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Van Hook, Matthew J; Thoreson, Wallace B (2014) Endogenous calcium buffering at photoreceptor synaptic terminals in salamander retina. Synapse 68:518-28
Hanneken, Anne M; Babai, Norbert; Thoreson, Wallace B (2013) Oral proton pump inhibitors disrupt horizontal cell-cone feedback and enhance visual hallucinations in macular degeneration patients. Invest Ophthalmol Vis Sci 54:1485-9
Van Hook, Matthew J; Thoreson, Wallace B (2013) Simultaneous whole-cell recordings from photoreceptors and second-order neurons in an amphibian retinal slice preparation. J Vis Exp :
Jackman, Skyler L; Babai, Norbert; Chambers, James J et al. (2011) A positive feedback synapse from retinal horizontal cells to cone photoreceptors. PLoS Biol 9:e1001057
Burkhardt, Dwight A; Bartoletti, Theodore M; Thoreson, Wallace B (2011) Center/surround organization of retinal bipolar cells: High correlation of fundamental responses of center and surround to sinusoidal contrasts. Vis Neurosci 28:183-92
Bartoletti, Theodore M; Thoreson, Wallace B (2011) Quantal amplitude at the cone ribbon synapse can be adjusted by changes in cytosolic glutamate. Mol Vis 17:920-31
Mercer, A J; Rabl, K; Riccardi, G E et al. (2011) Location of release sites and calcium-activated chloride channels relative to calcium channels at the photoreceptor ribbon synapse. J Neurophysiol 105:321-35
Margalit, Eyal; Babai, Norbert; Luo, Jianmin et al. (2011) Inner and outer retinal mechanisms engaged by epiretinal stimulation in normal and rd mice. Vis Neurosci 28:145-54
Mercer, Aaron J; Chen, Minghui; Thoreson, Wallace B (2011) Lateral mobility of presynaptic L-type calcium channels at photoreceptor ribbon synapses. J Neurosci 31:4397-406
Krizaj, David; Mercer, Aaron J; Thoreson, Wallace B et al. (2011) Intracellular pH modulates inner segment calcium homeostasis in vertebrate photoreceptors. Am J Physiol Cell Physiol 300:C187-97

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