Photoreceptors transmit their light responses across the first synapse in the retina by regulating the continuous release of glutamate-containing vesicles. The mechanisms by which light-evoked changes in membrane potential regulate synaptic transmission from photoreceptors are not well understood. We propose experiments to analyze the biophysical mechanisms of release from photoreceptors. Synaptic release from photoreceptors involves both fast transient and slow sustained components of release. Sustained release is important for shaping post-synaptic responses to slow changes in illumination and transient release contributes more to responses at abrupt light offset.
In Aim 1, we test whether sustained and transient components of release are both due to release from the synaptic ribbon or whether non-ribbon synaptic release sites are also involved.
In Aim 2, we determine how voltage-dependent changes in release probability, the size of the releasable pool of vesicles, and the rate of vesicle replenishment interact to shape sustained and transient post-synaptic responses to light and dark at the cone synapse.
In Aim 3, we test whether quantal synaptic currents evoked by release of individual synaptic vesicles are regulated by changes in cytosolic glutamate levels at the cone synapse. Understanding the mechanisms of synaptic release from photoreceptors is important for understanding basic mechanisms of vision and how vision is disrupted by mutations in synaptic proteins or mis-regulation of glutamate release. Understanding normal retinal physiology is also important for designing therapies to restore normal retinal function to diseased eyes using retinal stem cells or prosthetic devices.

Public Health Relevance

This project studies the mechanisms by which visual signals are transmitted to downstream neurons at the first synapse in the retina. In addition to providing a better understanding of early visual processing by the retina, understanding the mechanisms by which rod and cone photoreceptors release the neurotransmitter glutamate is necessary to understand how mutations in synaptic proteins or mis-regulation of glutamate release lead to eye disease and vision loss. An understanding of normal retinal physiology is also needed for restoring vision to diseased eyes by the use of retinal stem cells, prosthetic devices, or other means.

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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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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