characterized. SV-associated proteins that become 
autoantigens in the human stiff-man syndrome were 
characterized. 
During the process of neuron communication, the 
sender cell, upon excitation, releases neurotransmit- 
ters by calcium-dependent exocytosis of synaptic 
vesicles, and the mechanisms of neurotransmitter 
storage and release are under study by Associate In- 
vestigator Reinhard Jahn, Ph.D. (Yale University) 
and his colleagues. Synaptic vesicles are retrieved 
by endocytosis and are re-formed within the nerve 
terminal after passing through intermediate stages 
that probably include clathrin-coated vesicles and 
endosomes. Synaptic vesicles contain a group of spe- 
cific membrane protein families with unique struc- 
tural properties. The vesicle protein synaptotagmin 
was found to bind calcium ions at physiologically 
relevant concentrations, accompanied by an inter- 
action with phospholipid membranes. Therefore 
the protein is a candidate for being the exocytotic 
calcium ion receptor. The role of small GTP- 
binding proteins of the ras superfamily in vesicular 
membrane traffic was examined. Several of the pro- 
teins appear to function in exocytosis and mem- 
brane recycling of synaptic vesicles. Their mecha- 
nism of action remains to be clarified, but they may 
control individual steps of the vesicle cycle. 
Associate Investigator Richard H. Scheller, Ph.D. 
(Stanford University) and his colleagues examine 
the molecular mechanisms of brain development 
and function. They are particularly interested in the 
formation and function of the synapse, the special- 
ized region of cells responsible for converting the 
electrical impulse of an action potential into a chem- 
ical signal that travels between cells. Many diseases 
are the result of synaptic dysfunction, and many 
drugs act to modulate various aspects of synapse 
function. Agrin, a protein localized at the nerve 
muscle synapse, acts to concentrate neurotransmit- 
ter receptors in the proper place during develop- 
ment. Dr. Scheller's group has characterized the 
agrin protein and gene. They have now turned their 
attention to the mechanism of agrin action during 
mammalian development. Many of the molecules 
associated with synaptic vesicles are thought to regu- 
late the release of neurotransmitters. To understand 
these molecules better, the group has isolated 
cDNAs encoding the proteins. They are studying the 
roles of synaptic vesicle-associated proteins in the 
central nervous system. 
Senior Investigator Eric R. Kandel, M.D. (Colum- 
bia University) and his colleagues study elementary 
forms of learning and memory. During the past year 
they focused on the molecular switch that leads to 
the activation of long-term memory storage in Aply- 
sia. In addition, they have begun to explore some 
molecular mechanisms contributing to long-term 
potentiation in the hippocampus, a model of learn- 
ing in the mammalian brain. 
Learning is thought to involve the strengthening 
of specific synapses, the points of contact at 
which one nerve cell transfers information to an- 
other, so that this information transfer between 
nerve cells becomes more efficient. A phenomenon 
called long-term potentiation (LTP), intensively 
studied by neurobiologists, represents a long-lasting 
strengthening of synapses that occurs when those 
synapses are used repeatedly. LTP is widely believed 
to represent the cellular change underlying learn- 
ing, but the evidence for this remains equivocal. 
Mutant mice have been produced that lack a single 
enzyme that normally is concentrated at synapses. 
These mice are found to be deficient in LTP and also 
in a particular type of learning associated with the 
brain structures in which LTP is usually most promi- 
nent. These experiments of Investigator Charles F. 
Stevens, M.D., Ph.D. (Salk Institute) and his col- 
leagues, including the laboratories of Dr. Susumu 
Tonegawa and of Dr. Jeanne Wehner, support the 
hypotheses that LTP is a cellular mechanism of 
memory. 
Studies in the laboratory of Investigator Thomas 
M. Jessell, Ph.D. (Columbia University) over the 
past year have focused on the cellular interactions 
that control the early organization of the vertebrate 
nervous system. The identity of cells and their posi- 
tion within the neural tube appear to be controlled 
by inductive signals that derive from two ventral 
midline cell groups, the notochord and floor plate. 
Removal of these two cell groups leads to the loss of 
ventral cell types, and placing them adjacent to the 
dorsal neural tube leads to the ventralization of dor- 
sal regions. To understand the mechanisms by 
which cell identity and positions are determined by 
midline-derived signals, a search has been per- 
formed for genes that control the identity of floor 
plate cells and motoneurons. Two transcription fac- 
tors have been identified that define early stages of 
floor plate and motoneuron differentiation, and 
misexpression of one of these genes leads to changes 
in neural cell fate. In addition, a novel growth factor 
has been identified that is expressed in the neural 
tube and is a member of the transforming growth 
factor-;S family. This factor is restricted to dorsal re- 
gions of the neural tube and may be involved in the 
control of cell differentiation along the dorsoventral 
axis of the neural tube. 
Investigator Edward B. Zifi", Ph.D. (New York Uni- 
versity) and his colleagues have studied the regula- 
tion of gene activity during neuronal differentiation 
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