How do synaptic vesicles fuse with the plasma membrane? How are the components of the synaptic vesicle recycled? To answer these questions we propose to use genetic and cell biological techniques to identify and characterize proteins required for synaptic function in the nematode Caenorhabditis elegans. So far we have identified eleven genes that are required for neurotransmission in C. elegans. First, ric-5 and ric-7, two of these eleven genes, will be characterized at a molecular level. Null alleles will be isolated, these genes cloned, and the subcellular location of their gene products characterized. Finally, the synaptic morphology and the distribution of synaptic vesicle components in ric-5 and ric-7 mutants will be characterized. Second,new loci that function at the synapse will be identified. It is likely that mutations that eliminate all synaptic function will be lethal. We have devised a screen that can isolate both viable and lethal mutations that affect neurotransmission. This screen is even more powerful since it selects for such mutations by pharmacologically eliminating wild-type animals. Viable and lethal mutations from this screen that specifically disrupt nervous function will be genetically characterized. In summary, these genetic studies will complement existing biochemical studies of the synapse in two ways: (l) The proposed screens will identify new proteins that function in the synapse. These results will aid researchers using biochemical approaches because vertebrate homologs of these proteins can be identified. The activity of these proteins can then be tested in cell free assays that reconstitute vesicular exocytosis in vitro. (2) The analysis of the synaptic defects in mutants provides functional data about the role of particular proteins in neurotransmission in vivo. Together, these results will significantly advance our understanding of the molecular events involved in the exocytosis and endocytosis of synaptic vesicles. These basic studies may provide reagents that eventually can be used to alleviate the symptoms of myasthenia gravis, amyotrophic lateral sclerosis, and Alzheimer's Disease. In addition, we have found that at least three of the genes isolated in our screens seem to affect endocytosis at the nerve terminal. Endocytosis is the most common mechanism of viral entry into cells. The mechanisms of endocytosis elucidated in this proposal may provide a clearer understanding of the mechanisms of viral infection, particularly those that attack neurons or cause motor disease such as Herpes or HIV.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurology C Study Section (NEUC)
Program Officer
Baughman, Robert W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Schools of Arts and Sciences
Salt Lake City
United States
Zip Code
Watanabe, Shigeki; Mamer, Lauren Elizabeth; Raychaudhuri, Sumana et al. (2018) Synaptojanin and Endophilin Mediate Neck Formation during Ultrafast Endocytosis. Neuron 98:1184-1197.e6
Kurshan, Peri T; Merrill, Sean A; Dong, Yongming et al. (2018) ?-Neurexin and Frizzled Mediate Parallel Synapse Assembly Pathways Antagonized by Receptor Endocytosis. Neuron 100:150-166.e4
Topalidou, Irini; Chen, Pin-An; Cooper, Kirsten et al. (2017) The NCA-1 and NCA-2 Ion Channels Function Downstream of Gq and Rho To Regulate Locomotion in Caenorhabditis elegans. Genetics 206:265-282
Chen, Bojun; Liu, Ping; Hujber, Edward J et al. (2017) AIP limits neurotransmitter release by inhibiting calcium bursts from the ryanodine receptor. Nat Commun 8:1380
German, Christopher L; Gudheti, Manasa V; Fleckenstein, Annette E et al. (2017) Brain Slice Staining and Preparation for Three-Dimensional Super-Resolution Microscopy. Methods Mol Biol 1663:153-162
Jang, SoRi; Nelson, Jessica C; Bend, Eric G et al. (2016) Glycolytic Enzymes Localize to Synapses under Energy Stress to Support Synaptic Function. Neuron 90:278-91
Bend, Eric G; Si, Yue; Stevenson, David A et al. (2016) NALCN channelopathies: Distinguishing gain-of-function and loss-of-function mutations. Neurology 87:1131-9
Li, Pengpeng; Merrill, Sean A; Jorgensen, Erik M et al. (2016) Two Clathrin Adaptor Protein Complexes Instruct Axon-Dendrite Polarity. Neuron 90:564-80
Yogev, Shaul; Cooper, Roshni; Fetter, Richard et al. (2016) Microtubule Organization Determines Axonal Transport Dynamics. Neuron 92:449-460
Geisler, Florian; Gerhardus, Harald; Carberry, Katrin et al. (2016) A novel function for the MAP kinase SMA-5 in intestinal tube stability. Mol Biol Cell 27:3855-3868

Showing the most recent 10 out of 71 publications