The synapse is a shotgun - New model challenges textbook definition

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The synapse is a shotgun - New model challenges textbook definition

16 Jul 2005 Medical News Today

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

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.

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.

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. "

Medical Institute

www.hhmi.org