In sensory neurons of the eye and inner ear the neurotransmitter, glutamate, is released at active zones in a graded and continuous manner. In these neurons specialized structures have evolved, known as synaptic ribbons. Synaptic ribbons are osmiophilic proteinaceous structures that tether synaptic vesicles near active zones. Because of their morphology, location within the cells and the cell types where they are found, these organelles are likely essential for the continuous release of glutamate;how ribbons aid in this task, however, remains unclear. The focus of this grant is to study the role of synaptic ribbons in sensory synaptic transmission, with the long term goal to resolve the temporal sequence of molecular and cellular events that are involved in the release of neurotransmitter from these important cells. To do this we use a combination of electrophysiology, fluorescence and biochemical tools to study the properties of synaptic transmission from retinal bipolar cells.
Aim 1 is to investigation the properties of spontaneous and multi-vesicular release from the mouse rod bipolar cell synapse to determine the role of the ribbon in coordinating multi-vesicular release and to investigate the relationship between vesicles involve in evoked release and those involved in spontaneous release.
In Aim 2, we propose to investigate modulation of synaptic transmission from ribbon synapses by calcium calmodulin kinase ii.
In Aim 3, we investigate the role of the ribbon in priming vesicles for continuous neurotransmitter release. Understanding ribbon function may provide clues to help understand diseases that specifically affect vision and hearing, such as Usher syndrome. In addition, the fundamental understanding of presynaptic processes in these specialized neurons will have broader implications for neuronal communication in general and thus, may contribute to our understanding of various aspects of mental health and neurological disorders.

Public Health Relevance

In the retina and inner ear, primary sensory information is transmitted at specialized synapses, which transmit high rates of information in the form of neurotransmitter release in a graded manner. These neurons have evolved specialized structures to aid in this task and we aim to understand what these structures do for these cells. Understanding these synapses will ultimately aid in understanding how visual and auditory information is processed and communicated to the brain and will provide clues to help understand diseases that specifically affect vision and hearing.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014990-11
Application #
8523872
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Greenwell, Thomas
Project Start
2003-08-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
11
Fiscal Year
2013
Total Cost
$395,438
Indirect Cost
$157,938
Name
Yale University
Department
Physiology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Mehta, Bhupesh; Ke, Jiang-Bin; Zhang, Lei et al. (2014) Global Ca2+ signaling drives ribbon-independent synaptic transmission at rod bipolar cell synapses. J Neurosci 34:6233-44
Lv, Caixia; Zenisek, David (2014) Big minis from hair cells: mechanism and function. Neuron 83:1229-31
Grabner, Chad P; Zenisek, David (2013) Amperometric resolution of a prespike stammer and evoked phases of fast release from retinal bipolar cells. J Neurosci 33:8144-58
Mehta, Bhupesh; Snellman, Josefin; Chen, Shan et al. (2013) Synaptic ribbons influence the size and frequency of miniature-like evoked postsynaptic currents. Neuron 77:516-27
Xu, Hong-ping; Furman, Moran; Mineur, Yann S et al. (2011) An instructive role for patterned spontaneous retinal activity in mouse visual map development. Neuron 70:1115-27
Francis, Adam A; Mehta, Bhupesh; Zenisek, David (2011) Development of new peptide-based tools for studying synaptic ribbon function. J Neurophysiol 106:1028-37
An, Seong J; Grabner, Chad P; Zenisek, David (2010) Real-time visualization of complexin during single exocytic events. Nat Neurosci 13:577-83
Snellman, Josefin; Zenisek, David; Nawy, Scott (2009) Switching between transient and sustained signalling at the rod bipolar-AII amacrine cell synapse of the mouse retina. J Physiol 587:2443-55
Joselevitch, Christina; Zenisek, David (2009) Imaging exocytosis in retinal bipolar cells with TIRF microscopy. J Vis Exp :
Coggins, Michael; Zenisek, David (2009) Evidence that exocytosis is driven by calcium entry through multiple calcium channels in goldfish retinal bipolar cells. J Neurophysiol 101:2601-19

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