Secretory Pathways in Neurons 
Thomas C. Siidhof, M.D. — Investigator 
Dr. Siidhof is also Professor of Molecular Genetics at the University of Texas Southwestern Medical Center 
at Dallas. He received his M.D. degree and his doctorate from the Georgia Augusta University of Gottingen, 
FRG. He obtained postdoctoral training first with Victor Whittaker at the Max Planck Institute for 
Biophysical Chemistry, Gottingen, and then with Michael Brown and Joseph Goldstein in Dallas. 
NEURONS communicate with one another by 
means of chemical signals. The known com- 
munication pathways between neurons are of sev- 
eral kinds: 
• Fast, point-to-point transmission of signals 
between neurons occurs at the synapse. 
• Long-lasting modulatory signals that often 
reach many cells are transmitted outside of syn- 
apses by neuropeptides and other mediators. 
• Short-range diffuse signals are probably 
spread by lipophilic messengers, such as nitric 
oxide or arachidonic acid. 
Of these pathways, signaling between neurons 
at the synapse is quantitatively the major form of 
cell-to-cell communication in the central ner- 
vous system. Synapses are abundant in the ner- 
vous system, and their activity provides the basis 
of brain function. However, the slow communica- 
tion pathways are clearly an essential counterpart 
to the fast point-to-point signals. The coexistence 
of different signaling pathways in the same neu- 
ron increases the complexity of the neuronal 
networks. Brain function will clearly not be 
understood until we gain insight into the molecu- 
lar mechanisms that govern these signaling 
pathways. 
Work in our laboratory addresses the question 
of how nerve cells send out chemical signals. We 
are concentrating on the synapse as the most 
abundant signaling pathway. Here the chemical 
signals, the neurotransmitters, are prepackaged 
in unique cellular organelles called synaptic vesi- 
cles and released from the presynaptic neuron by 
secretion. This secretion is achieved by exocyto- 
sis, the fusion of synaptic vesicles with the synap- 
tic cell membrane. After fusion the empty synap- 
tic vesicles are quickly re-endocytosed and 
refilled with neurotransmitter. They become 
competent for secretion again in a short time, al- 
lowing the neurons to fire rapidly. 
We have taken two avenues to the exploration 
of the molecular basis of signal transmission at 
the synapse. The first approach has been to study 
synaptic vesicles and their components as the 
central organelle in neurotransmitter release. 
The second approach consists of a characteriza- 
tion of the presynaptic plasma membrane as the 
point of signal release. 
Characterizing the molecular components of 
synaptic vesicles constitutes a long-term project 
that we are largely carrying out in collaboration 
with Reinhard Jahn (HHMI, Yale University). 
This project has led to the molecular characteriza- 
tion of more than 10 synaptic vesicle proteins, 
which together account for approximately one- 
third to one-half of the total vesicle protein by 
mass. The goal of this project is twofold. 
First, we would like to achieve a complete de- 
scription of the synaptic vesicle in molecular 
terms. This is not only a precondition to any even- 
tual understanding of how the synaptic vesicle 
pathway works, but would also provide the first 
molecular anatomy of an organelle. 
Second, we would like to explore the functions 
of each vesicle protein in neurotransmitter re- 
lease, using biochemical and genetic techniques. 
This part of the project has progressed to the 
point that interesting biochemical properties of 
several vesicle proteins have been elucidated. 
Moreover, the feasibility of mouse genetics to 
probe the functions of these proteins has been 
demonstrated. For example, we have recently 
shown that a synaptic vesicle protein named syn- 
aptotagmin binds Ca^"^ and phospholipids in a 
ternary complex at physiologic Ca^"^ concentra- 
tions. This result suggests a function for synapto- 
tagmin in synaptic vesicle fusion, a possibility 
now being explored in transgenic mice. 
Another approach we are pursuing to elucidate 
synapse function is the study of the presynaptic 
plasma membrane. The membrane serves two ba- 
sic functions. It binds synaptic vesicles and fuses 
with them in a Ca^"^-dependent manner, thereby 
releasing neurotransmitter; and it contacts the 
postsynaptic site and aligns pre- and postsynaptic 
membranes with each other. Both functions 
are probably performed by specific protein 
components. 
To identify a component of the presynaptic 
plasma membrane that may be involved in its 
functions, we have studied the receptor for a neu- 
rotoxin called a-latrotoxin. This protein, derived 
from venom of the black widow spider, binds spe- 
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