Salk scientists overturn a dogma of nerve cell communication

 

La Jolla, CA - Every neurobiology textbook invariably states that nerve cells 
communicate with each other through synapses, the specialized cell-cell 
contacts found at the end of the cells' threadlike extensions. In this week's 
journal Science, researchers at the Salk Institute for Biological Sciences 
and the University of California at San Diego report that nerve cells, or 
neurons, may not have to rely on traditionally defined synapses to "talk" to 
each other. 

The new study indicates that nerve cells can also release neurotransmitters 
outside of synapses. Neurotransmitters are the chemical messengers that nerve 
cells use to shuttle outgoing signals to adjacent neurons. Salk scientists 
refer to the release of neurotransmitters outside of synapses as "ectopic 
neurotransmission". 


Cell-cell communications in other parts of the nervous system may also rely on 
ectopic neurotransmission, the new study suggests. This finding is an 
additional challenge to the descriptions of neuronal signal transmission 
found in neurobiology textbooks. 


"Our results opened up the possibility that neurons can communicate many other 
ways not just at the traditional places that are defined by their anatomy," 
says lead investigator Terrence J. Sejnowski, who heads the Crick-Jacobs 
Center for Computational and Theoretical Biology at the Salk Institute. To 
investigate cell-to-cell communication in the nervous system, Sejnowski and 
his colleagues developed a computer model simulating signal transmission at a 
particular synapse in chick embryos. The computer model convinced Sejnowski 
and his collaborators that it may be time to rethink cell-to-cell 
communication in the nervous system. 


In the past, the suggestion that neurotransmitters could be released and find 
their targets outside of clearly defined synapses, was considered an almost 
heretical notion. 


A unique collaboration between anatomists and physiologists at the University 
of California in San Diego and theoretical neurobiologists at the Salk 
Institute was needed to rethink the standard model of neurotransmission. 
Darwin Berg in the Biology Department provided the physiological data upon 
which the model was based and Mark Ellisman in the Department of Neuroscience 
created a high-resolution reconstruction of the structure using high-voltage 
electron microscopy. 


"In addition to the discovery of ectopic transmission this is the very first 
time that all these elements have been brought together," says Sejnowski. 
"Combining mathematical modeling with physiological, anatomical and 
behavioral data is the future of neurobiology. It allows us to draw 
conclusions that we could not have reached in any other way." 


According to textbooks, nerve signals are transmitted from cell to cell only 
via specialized junctions. The transmitting neuron has a slightly swollen 
terminal point, which houses small vesicles that are filled with 
neurotransmitter. Upon arrival of a nerve signal, the vesicles spill their 
content into the narrow space between two cells. The released 
neurotransmitter molecules flow across the gap to the adjacent nerve cell and 
bind to specific receptor proteins on the receiving cell's membrane. If the 
receiving cell is a neuron, the binding of the neurotransmitter will generate 
an electrical impulse that travels along the length of the cell. If the 
receiving cell is a muscle cell, it will be stimulated to contract. 


Based on high-resolution electron microscope images, research fellow Jay S. 
Coggan and scientist Thomas M. Bartol, the co-first authors of the Science 
paper, created a highly accurate computer model simulation of the giant chick 
embryo synapse that connects nerve fibers originating in the brain with the 
neuron that controls the size of the pupil and the shape of the eye lens. 
This particular synapse is a favorite model for the study of synaptic 
transmission since the neurons forming what is known as the ciliary ganglion 
are rather simple, easily accessible and nerve impulses can be recorded from 
either the presynaptic or the postsynaptic element or both. 


Such recordings of nerve signals tipped off the researchers to the possibility 
that receptors outside of the synapse were routinely activated. But where did 
the necessary neurotransmitter molecules come from? 


Coggan and Bartol then simulated the release of neurotransmitter from single 
vesicles located within synapses as well as from vesicles located outside 
traditional synaptic junctions in what they called "ectopic release". Next 
they compared their predictions with actual recordings from living cells. "We 
could only match the physiological results when we allowed 90 per cent of the 
release to occur outside of synapses," says Bartol who remarks in a 
philosophical aside: "Ectopic release is an interesting term because it means 
'out of place' but of course in nature nothing is out of place." 


"I think it challenges how we define synapses. There might still be synapses 
that fit the old definition but that might not be the only way that cells 
communicate," adds Coggan. 


The necessary machinery, for one, has always been there. Scientists had known 
for a long time that all over the nervous system neurotransmitter-filled 
vesicles, SNARE-complexes responsible for fusing vesicles with cell membranes 
and neurotransmitter receptors were sitting outside of synapses but nobody 
knew what their function was. "A lot of the signals we recorded from the 
ganglion indicated that receptors that were considered perisynaptical were 
being activated in large numbers," remembers Coggan. "For me it was very 
gratifying when the computer model verified our suspicions." 


Coggan points out that traditional and ectopic neurotransmission might simply 
serve different functions since acetylcholine, the neurotransmitter bridging 
the synaptic gap in the ciliary ganglion, activates two different types of 
nicotinic receptors: Alpha7-acetylcholine receptors (α7-AchR) and alpha3- 
acetylcholine receptors (α3-AchR) that differ in their biophysical properties 
and their spatial distribution. α3-AchRs cluster at synaptic sites on the 
cell body whereas α7-AchRs are found in perisynaptic areas. Ectopic 
transmission activates almost exclusively the latter. 


"We are just beginning to appreciate the diversity and complexity of signaling 
in the brain. In the past we have been guided by very simple model systems 
like the neuromuscular junction. But in the brain there is an enormously more 
complex set of connections and demands that the system has to be able to 
perform. Evolution could have created entirely new possibilities," says 
Sejnowski. 


The Crick-Jacobs Center for Computational and Theoretical Biology, funded by a 
generous gift from Joan and Irwin Jacobs, uses computer-based computational 
methods to mine the enormous amount of data on the composition of genes and 
proteins in the brain as well as the neural networks that regulate 
information processing. The ultimate goal is to generate theoretical models 
that explain how the brain works. 

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