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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010542-17
Application #
8306863
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
1996-06-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
17
Fiscal Year
2012
Total Cost
$352,836
Indirect Cost
$128,316
Name
University of Nebraska Medical Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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
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 :
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
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
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
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
Plog, Stephanie; Klymiuk, Nikolai; Binder, Stefanie et al. (2015) Naturally Occurring Deletion Mutants of the Pig-Specific, Intestinal Crypt Epithelial Cell Protein CLCA4b without Apparent Phenotype. PLoS One 10:e0140050
Van Hook, Matthew J; Thoreson, Wallace B (2015) Weak endogenous Ca2+ buffering supports sustained synaptic transmission by distinct mechanisms in rod and cone photoreceptors in salamander retina. Physiol Rep 3:
Thoreson, Wallace B (2015) Horizontal slices of mouse retina expose horizontal cells and their properties (Commentary on Feigenspan & Babai). Eur J Neurosci 42:2613-4
Van Hook, Matthew J; Thoreson, Wallace B (2015) Unconventional Transmission at Conventional Synapses of an Inhibitory Interneuron. Neuron 87:463-5

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