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July 15, 2005
Synapses May Fire Neurotransmitters Like a Shotgun
Researchers have constructed a new detailed map of the
three-dimensional terrain of a synapse — the junction between neurons
which are critical for communication in the brain and nervous system.
The “nano-map,” which shows the tiny spines and valleys
resolved at nanometer scale, or one-billionth of a meter, has already
proven its worth in changing scientists' views of the synaptic
landscape.
Using the map as a guide, the research team, led by Howard Hughes
Medical Institute investigator Terrence Sejnowski, has developed a
biologically accurate computer simulation of synaptic function. The
simulation combines 3-D electron microscope maps with computer
simulation and physiological measurements from real neurons. Their
in silico modeling indicates that the synapse may behave more
like a shotgun than a rifle when it comes to firing the
neurotransmitters involved in neuronal communication.
“We will continue to develop this new picture of the synapse to convince doubters, because this is such a different way of looking at how the synapse functions.”
Terrence J. Sejnowski
The textbook view of the synapse describes it as a place where
rifle-like volleys of neurotransmitter are launched from one defined
region of the sending neuron to another defined target on the receiving
neuron. In contrast, the new data suggest that synapse can act like a
shotgun, firing buckshot-like bursts of neurotransmitter to reach
receptors arrayed beyond the known receiving sites. The researchers say
that right now they have little idea of how the synaptic shotgun
functions.
 | | | | |  | | | | | |  |  | Monte Carlo Model of the Ciliary Ganglion
Communication between neurons in the brain occurs at synapses... more | |
| | | | | | |  | | Monte Carlo Model of the Ciliary Ganglion
This video shows a realistic computer simulation of neurotransmission in a chick ciliary ganglion synapse... watch video
Images: Thomas Bartol, Jr. | |
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The research was published in the July 15, 2005, issue of the
journal Science. Sejnowski, who is at The Salk Institute, and
colleagues Darwin Berg and Mark Ellisman, both of the University of
California, San Diego, led the research team, which also included
co-authors from Carnegie Mellon University and the University of
Pittsburgh.
In the collaborative studies, Ellisman and his colleagues first used
electron microscopic tomography — the microscopist's equivalent of a
CAT scan — to create a detailed 3-D map of the synapse of a chick
ciliary ganglion. This ganglion is a cluster of neurons that connect
the brain to the iris of the eye. It launches the neurotransmitter
acetylcholine from sac-like vesicles across the synapse to two types of
receptors, called alpha 7 and alpha 3.
Sejnowski and his colleagues transformed their map into a functional
computer model by incorporating the physiological details of
neurotransmitter release sites and receptors. The researchers then
compared the behavior of the model under different scenarios with the
electrophysiological behavior of actual ganglia measured in Berg's
laboratory.
The results, said Sejnowski, provide evidence for a different
concept of the synapse. “The image of this ganglion is not one of
a simple synapse with a single release site, but multiple release
sites. And it shows alpha 3 receptors within the postsynaptic region,
but alpha 7 receptors outside this region. Our model showed that if we
assumed that neurotransmitter is released only from vesicles in active
zones, where everybody thinks it is released, we get a very bad match
to actual properties of the neuron. But if we model broader
neurotransmitter release, where these alpha 7 receptors are located, we
can match the actual properties of the synapse very accurately.”
This type of broader neurotransmitter distribution is called ectopic
release.
“We can only be sure of data on this one type of neuron, the
ciliary ganglion,” said Sejnowski. “But we are confident
that this evidence points to ectopic release, and this means that you
can't really trust the traditional textbook view — in which all the
vesicles are released at the active zone — that's taken for granted
now.”
The function of shotgun neurotransmitter release is unknown, said
Sejnowski. “There's just nothing solid on our radar screen right
now,” he said. “There is speculation that ectopic release
represents some sort of spillover that neurons use under certain
circumstances. Or, it may be an alternative mode of neurotransmission
that neurons use at different points in their life cycle.”
Sejnowski and his colleagues have initiated further studies using their
simulation technique to confirm the ectopic release mechanism and
explore its possible functions.
“Although we are convinced that ectopic release exists, any
time you question an accepted concept, there will be doubt and
resistance,” said Sejnowski. “So, we will continue to
develop this new picture of the synapse to convince doubters, because
this is such a different way of looking at how the synapse
functions.” Sejnowski said that he and his collaborators will
extend their study to other types of synapses that are more complex and
difficult to study.
More broadly, said Sejnowski, the new 3-D modeling technique could
offer a powerful tool for understanding neurological disease, such as
myasthenia gravis, a common disorder in which a defect in nerve impulse
transmission results in muscle weakness. In this and other neurological
diseases, “there may be an anomaly at the receptor level, but it
is impossible to pinpoint the problem with existing techniques. With
our modeling technique, we can explore the detailed geometry of the
damaged tissue and ask how much of that anomaly is caused by the
geometry itself,” he said.
"Once we have pinned down where the real problem is, we can use the
model as a fantastic tool for drug discovery. We can tell drug
developers precisely where the anomaly is and where they should focus
drug discovery efforts."
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Versión en español
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Jennifer Michalowski
