1998 — 2021 |
Heidelberger, Ruth |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Mechanisms of Neurotransmission in Vertebrate Retina @ University of Texas Hlth Sci Ctr Houston
Calcium-regulated release of neurotransmitter is a fundamentally important process throughout the central nervous system. How this process is regulated presynaptically is not yet fully understood, but recent advances in the detection of synaptic vesicle fusion and neurotransmitter release, combined with the identification of putative proteins that either comprise or interact with the secretion machinery have now made such mechanistic investigations feasible. The long-range goal of this research project is to understand how the transfer of visual information between the outer and inner retina is regulated at the presynaptic level in retinal bipolar cells. The approach is to use a combination of biophysical techniques, including measurements of membrane capacitance and flash-photolysis of caged-calcium, in conjunction with probes designed to interact with SNARE proteins, to identify distinct stages of the secretion pathway in single synaptic terminals of retinal bipolar cells. The results of these experiments will guide the formation of a testable model of the late steps in neurotransmitter exocytosis at a ribbon synapse. Then, modulation of this secretory pathway by physiologically relevant neurotransmitters, neuropeptides, and second messenger systems will be examined to determine the extent to which they modulate synaptic release. Calcium, in addition to its role in initiating release, may effect other parts of the secretory pathway. Therefore, the actions of calcium and calcium- activated conductances on synaptic release and synaptic vesicle cycling will also be examined. Armed with this information, predictions will be made about the effects of local circuit interactions and previous stimulus history on the throughput of visual information from photoreceptors to the third-order neurons of the retina.
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2008 — 2012 |
Heidelberger, Ruth |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Neurotransmisson in Vertebrate Retina @ University of Texas Hlth Sci Ctr Houston
[unreadable] DESCRIPTION (provided by applicant): The long-term goal of this research program is to understand the mechanisms by which visual information is transferred across the vertebrate retina. Although the calcium-regulated release of neurotransmitter is a fundamental feature of synaptic communication, the presynaptic mechanisms that govern neurotransmitter release are not yet fully-understood. This is particularly true at the ribbon-style synapses of retinal photoreceptors and bipolar cells, which play pivotal roles in the throughput of visual information. In this research program, we examine mechanisms by which synaptic vesicle dynamics of bipolar cells and photoreceptors of the vertebrate retina are regulated. A combination of biophysical, molecular, and computational approaches are used. Specific goals are to characterize the roles of synaptic vesicle protein 2 (SV2), an integral synaptic vesicle protein, on neurotransmitter release from the mouse rod bipolar cell. A particular emphasis is to define the role of this protein in setting the gain of the rod bipolar cell synapse. The interplay between Ca2+ and other second messengers on the Ca2+-sensitivity of release and vesicle recruitment will also be examined. In addition, the roles of Ca2+ in vesicle recruitment, mobilization and release will be defined for photoreceptors. Detailed computational models of synaptic vesicle mobilization, recruitment and fusion will then be constructed for bipolar cells and photoreceptors. These models will allow us to perform in silico experiments that predict the pattern and extent of neurotransmitter release from various starting conditions. In addition, they will become instrumental in predicting at which step in the complex neuronal secretory pathway a particular manipulation has its effect. Together, the data obtained from this research program will not only reveal new insights into the regulation of the fundamental process of neurotransmitter release at retinal ribbon synapses, but will reveal novel ways by which the release of neurotransmitter is modulated so as to meet the needs of synaptic signaling under different levels of illumination. Furthermore, these results will position us to better determine and understand the role of specific synaptic proteins implicated in disorders of vision. PUBLIC HEALTH RELEVANCE: Results of this research program will enhance our understanding of how we see, providing information for the development of new treatments that will restore vision or prevent its further loss. In addition, it will provide general information about how neurons communicate that is critical for understanding brain diseases such as epilepsy, dementia and schizophrenia. [unreadable] [unreadable] [unreadable]
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