IV PROGRAM IN NEUROSCIENCE 
The Institute's Program in Neuroscience was ini- 
tiated in 1984. Investigators in this area are work- 
ing at The Johns Hopkins University; the University 
of California at Berkeley, at San Diego, and at San 
Francisco; the Massachusetts General Hospital; the 
Massachusetts Institute of Technology; the Univer- 
sity of Texas Southwestern Medical Center at Dal- 
las; Yale University; Columbia University; the Uni- 
versity of Pennsylvania; The Salk Institute for 
Biological Studies; the University of Washington; 
vhe State University of New York at Stony Brook; 
and Brandeis University. Among the topics under 
investigation are the development of the nervous 
system, the molecular basis of neurotransmission, 
the structure and function of receptors for neuro- 
transmitters, the mechanisms responsible for long- 
term changes in the nervous system, and the cellu- 
lar and molecular basis of certain neurological 
diseases. 
Senior Investigator Eric R. Kandel, M.D. (Colum- 
bia University) and his colleagues have continued 
to study elementary forms of learning and the rela- 
tionship between short- and long-term memory. 
During the past year they have examined three is- 
sues: 1) some of the molecular mechanisms of long- 
term memory, 2) the interactions between presyn- 
aptic neurons and target cells that lead to neuronal 
growth changes associated with long-term memory, 
and 3) cloning of potassium channels in Aplysia 
based on their homology to the Drosophila Shaker 
locus. 
Changes in synaptic effectiveness are believed to 
underlie all memory and learning. These changes 
are produced by modulating neural inputs to 
specific nerve cells that operate through receptor- 
mediated processes or signal transduction mech- 
anisms. Each of these transduction mechanisms 
can change the biochemical properties of the tar- 
get nerve cell through the generation of a sec- 
ond messenger that, in turn, activates secondary 
effectors such as protein kinases. Investigator 
James H. Schwartz, M.D., Ph.D. (Columbia Uni- 
versity) and his co-workers have examined the 
mechanisms by which these enzymes are altered 
in id^ntiiied Aplysia neurons that have been shown 
to mediate a simple form of learning and how 
these kinases are made to act long after the initial 
second messenger has been dissipated. The lab- 
oratory has discovered mechanisms for keeping 
the cAMP-dependent protein kinase and protein 
kinase C persistently active. These persistence 
mechanisms are important, because they may pro- 
vide for part of the molecular basis of learning and 
memory. 
Neurons communicate with one another at syn- 
apses, which are specialized points of contact be- 
tween the processes of one neuron and the cell 
body or dendrites of another. The presynaptic neu- 
ron transmits a signal by releasing one or more 
packets of a specific chemical, a neurotransmitter, 
from the ends of its processes; the neurotransmit- 
ter in turn is detected by specialized receptors on 
the surface of the postsynaptic or receiving neuron. 
This method of transmission is somewhat uncer- 
tain, however, because the release of the packets of 
neurotransmitter is a stochastic or random process. 
To understand neural signaling, then, the probabi- 
listic laws that govern neurotransmitter release 
must be elucidated. Technical difficulties have, 
however, prevented these laws from being thor- 
oughly investigated in synapses in the brain. By ex- 
ploiting some of the advantages of neural circuits 
that can be formed by neurons growing in cell cul- 
ture dishes, the laboratory of Investigator Charles F. 
Stevens, M.D., Ph.D. (Yale University) has been able 
to characterize this probabilistic release process 
that underlies neural signaling for one important 
class of synapse. 
In neurons the storage and secretion of neuro- 
transmitters is mediated by specialized cellular or- 
ganelles called synaptic vesicles. The recent investi- 
gations of Associate Investigator Thomas C. Siidhof, 
M.D. (University of Texas Southwestern Medical 
Center at Dallas) have focused on the composition 
of the membranes of such vesicles. Using molecular 
cloning techniques, he and his colleagues have suc- 
ceeded in elucidating the primary structures of sev- 
eral vesicle membrane proteins and are providing 
tools to study the functions of these proteins in the 
biogenesis and exocytosis of synaptic vesicles. Their 
work is relevant not only for an understanding of 
vesicle biogenesis and targeting in neurons but also 
for the elucidation of the ubiquitous recycling of 
membrane that occurs in all secretory cells. 
The research in the laboratory of Associate Inves- 
tigator Richard L. Huganir, Ph.D. (The Johns Hop- 
kins University) is directed toward understanding 
the molecular mechanisms that underlie the modu- 
lation of synaptic function. Dr. Huganir's laboratory 
is using the nicotinic acetylcholine receptor, which 
is by far the best characterized neurotransmitter re- 
ceptor, as a model system to study the role of pro- 
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