Erik Jorgensen
Professor of Biology
B.S. University of California, Berkeley
Ph.D. University of Washington
Erik Jorgensen's Lab Page
Erik Jorgensen's PubMed Literature Search
Erik Jorgensen's Howard Hughes Medical Institute Page
Research
What is the molecular nature of memory? It seems that memory is encoded by changes in the strength of synapses. It is our goal to identify the molecules that function at the synapse and to understand how the activities of these molecules are changed to strengthen or weaken a synapse. To identify such molecules we have undertaken a genetic analysis of neurotransmission in the nematode Caenorhabditis elegans. C. elegans is particularly advantageous for genetic studies of the nervous system for several reasons: First, mutants with defective synapses are viable and can be studied as adults. Second, we can select for mutants with defective neurotransmission using drug resistance screens. Third, we can characterize mutant synapses at the ultrastructural and electrophysiological level. Fourth, the entire genomic sequence of the nematode has been completed; and knockouts of many genes have been generated; this greatly expedites the characterization of genes.
Our goal is to identify the genes required for synaptic function. Such genes are likely to regulate synaptic vesicle dynamics. When a neuron fires an action potential, calcium ions flow into the axonal terminus of the presynaptic cell. Calcium influx causes synaptic vesicles to fuse with the plasma membrane and to release neurotransmitter to the surface of the neighboring cell.
What is the molecular mechanism of calcium sensing and vesicle fusion? In our screens we have identified synaptotagmin and the SNARE proteins, the proteins thought to mediate these steps. In addition, we have identified other proteins such as UNC-13 and UNC-18. Our electrophysiological and ultrastructural analysis indicates that these proteins are required for vesicle fusion. One model is that these proteins are required to convert the SNARE protein syntaxin into the open configuration. We tested this model and determined that UNC-13 was required to open syntaxin but UNC-18 was not.
What is the molecular mechanism of synaptic vesicle retrieval? Once synaptic vesicles have fused with the plasma membrane, the components must be retrieved from the plasma membrane via endocytosis to regenerate a reserve pool of vesicles. We are studying clathrin-mediated endocytosis and lipid modifying proteins that are essential for endocytosis.
What are the mechanisms for synaptic plasticity? We are currently studying the role of GTPases in potentiating or weakening synaptic strength. Our data indicate that Gq subunits of trimeric G proteins have novel targets beyond the lipid modifying enzymes of the canonical pathway.
What neurotransmitters function at synapses? GABA is the primary inhibitory neurotransmitter in vertebrate and invertebrate nervous systems. Our analysis of GABA has demonstrated that GABA is an excitatory neurotransmitter at both neurons and muscles in the nematode. Moreover, we have discovered that protons can act as a transmitter at some synapses. These studies suggest that there is an unforeseen richness to the molecular complexity of the nervous system - and hence the brain.
References
1. Hammarlund M, Nix P, Hauth L, Jorgensen EM, Bastiani MJ (2009) Axon regeneration requires a conserved MAP kinase pathway. Science 323:802-806
2. Sato K, Ernstrom G, Watanabe S, Weimer R, Chen CH, Sato M, Siddiqui A, Jorgensen EM, Grant B (2009) Differential requirements for clathrin in receptor-mediated endocytosis and maintenance of synaptic vesicle pools. Proc Natl Acad Sci USA 106:1139-1144
3. Gu M, Schuske K, Watanabe S, Baum P, Garriga G. Jorgensen EM (2008) 2 adaptin is not essential for synaptic vesicle recycling in C. elegans. Journal of Cell Biology 183:881-892
4. Frøkjær-Jensen C, Davis MW, Hopkins CE, Newmann B, Thummel JM, Olesen S-P, Grunnet M, Jorgensen EM (2008) Single copy insertion of transgenes in C. elegans. Nature Genetics 40:1375-1383
5. Davis MW, Morton J, Carroll D, Jorgensen EM (2008) Gene activation using FLP recombinase in C. elegans. PLoS Genetics 4(3) e1000028
6. Hammarlund M, Watanabe S, Schuske K, Jorgensen EM (2008) CAPS and syntaxin dock dense core vesicles to the plasma membrane in neurons. Journal of Cell Biology 180:483-491
7. Beg AP, Ernstrom G, Nix P, Davis MW, Jorgensen EM (2008) Protons act as a transmitter for muscle contraction in C. elegans. Cell 132:149-160
