The computational power of the brain depends on precise synaptic connections that link together billions of neurons. How changes in synaptic function mediate long lasting neuronal plasticity is a key question in modern neurobiology and likely to be important for understanding the pathogenesis associated with human cognitive disorders. Calcium influx into both pre- and post-synaptic neuronal compartments is a key determinant of synaptic transmission and long-term synapse potentiation. Presynaptically, calcium influx following an action potential initiates synaptic vesicle fusion and the release of neurotransmitters. Postsynaptically, calcium influx through neurotransmitter receptors triggers synapse specific potentiation. However, the molecular mechanisms that allow calcium influx to mediate synaptic information transfer is still being elucidated. The goal of this project is to characterize the function of the synaptotagmin family in calcium-dependent membrane trafficking on both sides of the synapse. Synaptotagmin 1 (Syt1) is a calcium-binding synaptic vesicle protein that functions as the fast calcium sensor for synchronous synaptic vesicle fusion. Although the basic functions of Syt 1 have now been identified, the mechanisms that underlie its activity are still unclear. Synaptotagmin 4 (Syt 4) is an evolutionary conserved member of the family that localizes to the postsynaptic compartment and is hypothesized to function in calcium-dependent postsynaptic vesicle fusion and the release of retrograde signals that mediate synaptic growth and plasticity. Characterizing Syt 4-dependent retrograde signaling will greatly facilitate our understanding of the role of postsynaptic vesicle fusion in neuronal plasticity. Our analysis will combine genetic manipulations available in Drosophila with molecular, biochemical, electrophysiological and morphological approaches to characterize how synaptotagmins mediate calcium-dependent membrane trafficking at synapses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040296-09
Application #
7739470
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
2000-07-01
Project End
2011-06-30
Budget Start
2009-12-01
Budget End
2011-06-30
Support Year
9
Fiscal Year
2010
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Guan, Zhuo; Bykhovskaia, Maria; Jorquera, Ramon A et al. (2017) A synaptotagmin suppressor screen indicates SNARE binding controls the timing and Ca2+ cooperativity of vesicle fusion. Elife 6:
Akbergenova, Yulia; Littleton, J Troy (2017) Pathogenic Huntington Alters BMP Signaling and Synaptic Growth through Local Disruptions of Endosomal Compartments. J Neurosci 37:3425-3439
Zhang, Yao V; Ormerod, Kiel G; Littleton, J Troy (2017) Astrocyte Ca2+ Influx Negatively Regulates Neuronal Activity. eNeuro 4:
Krench, Megan; Cho, Richard W; Littleton, J Troy (2016) A Drosophila model of Huntington disease-like 2 exhibits nuclear toxicity and distinct pathogenic mechanisms from Huntington disease. Hum Mol Genet 25:3164-3177
Harris, Kathryn P; Zhang, Yao V; Piccioli, Zachary D et al. (2016) The postsynaptic t-SNARE Syntaxin 4 controls traffic of Neuroligin 1 and Synaptotagmin 4 to regulate retrograde signaling. Elife 5:
Weiss, Kurt R; Littleton, J Troy (2016) Characterization of axonal transport defects in Drosophila Huntingtin mutants. J Neurogenet 30:212-221
Cho, Richard W; Buhl, Lauren K; Volfson, Dina et al. (2015) Phosphorylation of Complexin by PKA Regulates Activity-Dependent Spontaneous Neurotransmitter Release and Structural Synaptic Plasticity. Neuron 88:749-61
Whittaker, Roger G; Herrmann, David N; Bansagi, Boglarka et al. (2015) Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome. Neurology 85:1964-71
Lee, Jihye; Littleton, J Troy (2015) Transmembrane tethering of synaptotagmin to synaptic vesicles controls multiple modes of neurotransmitter release. Proc Natl Acad Sci U S A 112:3793-8
Piccioli, Zachary D; Littleton, J Troy (2014) Retrograde BMP signaling modulates rapid activity-dependent synaptic growth via presynaptic LIM kinase regulation of cofilin. J Neurosci 34:4371-81

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