One of the major forms of communication between neurons in the brain is that which occurs at chemical synapses. The control of synaptic communication is a crucial means by which the nervous system directs information flow in the brain. Understanding the detailed physiology of synaptic terminals in the central nervous system (CNS) will thus be critical to determining the nature of this control in both normal and diseased states of brain function. The long term objectives are to determine the mechanisms of control of synaptic transmission in the CNS. Traditional electrophysiological characterization gives a complex picture of a mixture of presynaptic and postsynaptic properties from an indeterminate number of synapses. Individual synaptic terminal properties remain poorly characterized. The optical tracer dye FM 1-43 labels synaptic vesicles specifically during membrane recycling; this allows one to cleanly separate presynaptic contributions to synaptic function and to obtain detailed information of presynaptic physiological parameters at the single synapse level.
Three specific aims are proposed: Characterize the control of synaptic vesicle exocytosis by extracellular Ca2+ in individual synaptic terminals during action potential stimulation and determine the role of specific Ca2+ channels in determining this control. Determine the maximal amount of exocytosis per action potential at individual synapses and how it is controlled. Examine the role of synaptotagmin-1 in the control of Ca2+-mediated exocytosis by measuring unitary presynaptic properties in neurons derived from synaptotagmin deficient mice. This work should lead to a much better understanding of the functioning of synaptic machinery, the major target of most therapies of CNS disorders such as epilepsy, depression, and schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036942-03
Application #
6126384
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Talley, Edmund M
Project Start
1997-12-01
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
3
Fiscal Year
2000
Total Cost
$269,423
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Chakrabarti, Rajarshi; Ji, Wei-Ke; Stan, Radu V et al. (2018) INF2-mediated actin polymerization at the ER stimulates mitochondrial calcium uptake, inner membrane constriction, and division. J Cell Biol 217:251-268
Cao, Mian; Wu, Yumei; Ashrafi, Ghazaleh et al. (2017) Parkinson Sac Domain Mutation in Synaptojanin 1 Impairs Clathrin Uncoating at Synapses and Triggers Dystrophic Changes in Dopaminergic Axons. Neuron 93:882-896.e5
Ashrafi, Ghazaleh; Ryan, Timothy A (2017) Glucose metabolism in nerve terminals. Curr Opin Neurobiol 45:156-161
de Juan-Sanz, Jaime; Holt, Graham T; Schreiter, Eric R et al. (2017) Axonal Endoplasmic Reticulum Ca2+Content Controls Release Probability in CNS Nerve Terminals. Neuron 93:867-881.e6
Pan, Ping-Yue; Marrs, Julia; Ryan, Timothy A (2015) Vesicular glutamate transporter 1 orchestrates recruitment of other synaptic vesicle cargo proteins during synaptic vesicle recycling. J Biol Chem 290:22593-601
Wragg, Rachel T; Gouzer, GĂ©raldine; Bai, Jihong et al. (2015) Synaptic activity regulates the abundance and binding of complexin. Biophys J 108:1318-1329
Rangaraju, Vidhya; Calloway, Nathaniel; Ryan, Timothy A (2014) Activity-driven local ATP synthesis is required for synaptic function. Cell 156:825-35
Armbruster, Moritz; Messa, Mirko; Ferguson, Shawn M et al. (2013) Dynamin phosphorylation controls optimization of endocytosis for brief action potential bursts. Elife 2:e00845
Kim, Sung Hyun; Ryan, Timothy A (2013) Balance of calcineurin A? and CDK5 activities sets release probability at nerve terminals. J Neurosci 33:8937-50
Ariel, Pablo; Ryan, Timothy A (2012) New insights into molecular players involved in neurotransmitter release. Physiology (Bethesda) 27:15-24

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