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RESEARCH INTERESTS
Genetic analysis of neurotransmission in C. elegans
Synaptic vesicle exocytosis and endocytosis
Vesicular neurotransmitter transporters
GABA receptors
Behavioral rhythms
Transposons
PUBLICATIONS
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; this greatly expedites the molecular
characterization of the genes identified in mutant
screens.
Our first goal is to identify the genes required for the
functioning of all synapses. 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. We have identified scores of genes that
are required for normal synaptic transmission. One of
these genes encodes the protein UNC-13. We have found
that UNC-13 is required to prime synaptic for release.
Another protein we study is synaptotagmin.
Synaptotagmin is an integral membrane protein of the
synaptic vesicle and is required for normal exocytosis.
To our surprise we found that synaptotagmin is also
required for the recycling of synaptic vesicles. Because
of this requirement, in synaptotagmin mutants
neuromuscular junctions are depleted of synaptic
vesicles. As we continue our genetic analysis of
the proteins required for synaptic function, a more
detailed understanding will emerge as to how these gene
products interact to regulate the release of synaptic
vesicles.
A second project in the lab is to identify the genes
required specifically for GABA function. GABA is the
primary inhibitory neurotransmitter in vertebrate and
invertebrate nervous systems. Understanding GABA
neurotransmission is of great medical importance since
GABA receptors are the target of anesthetic, anxiolytic,
anti-epileptic and anti-spasmodic drugs. We have
identified six genes required specifically for GABA
neurotransmission. These genes encode the GABA-
specific biosynthetic enzyme, the transporter required
for the packaging of GABA into synaptic vesicles, and the
GABA receptors on the postsynaptic cell. One of these
genes is required for a novel excitatory GABA function
and encodes a new type of GABA receptor.
Selected publications
Beg, A., and E.M. Jorgensen. 2003. An excitatory GABA receptor. Nature Neuroscience 6 (11) p.
Weimer, R., J.E. Richmond, W.S. Davis, J. Gritton, G. Hadwiger, M. Nonet and E.M. Jorgensen. 2003. Defects in synaptic vesicle docking in unc-18 mutants. Nature Neuroscience 6 (10) p.
Knobel, K., W. Davis and E.M. Jorgensen, and M. Bastiani. 2001. UNC-119 suppresses axon branching in C. elegans. Development 128: 4079-4092.
Bessereau, J.L., A. Wright, D.C. Williams, K. Schuske, M.W. Davis and E.M. Jorgensen. 2001. Mobilization of a Drosophila transposon in the Caenorhabditis elegans germ line. Nature 413, 70-74.
Richmond, J.E., R.M. Weimer, and E.M. Jorgensen. 2001. An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming. Nature 412, 338-341.
Harris, T.W., E. Hartwieg, H.R. Horvitz, and E.M. Jorgensen. 2000. Mutations in synaptojanin disrupt vesicle recycling. J Cell Biol 150, 589-600.
Hammarlund, M., W.S. Davis and E.M. Jorgensen. 2000. Mutations in β-spectrin disrupt axon outgrowth and sarcomere structure. J. Cell Biol. 149, 931-942.
Richmond, J.E., W.S. Davis, and E.M. Jorgensen. 1999. UNC-13 is required for synaptic vesicle fusion in C. elegans. Nature Neuroscience 2, 959-964.
Dal Santo, P., M.A. Logan, A.D. Chisholm and E.M. Jorgensen. 1999.The inositol trisphosphate receptor regulates a 50 second behavioral rhythm in C. elegans. Cell 98, 757-767.
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