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Zooming out from the atomic to the genomic level, Darnell's group searched for nerve cell proteins whose production is regulated by one RNA splicing molecule, called Nova. To do that, they used a gene microarray tool that would show which RNAs were present in a nerve cell when Nova was present but not when Nova was absent. They found 49 such RNAs and, surprisingly, found that some 80 percent of the corresponding proteins function at the synapse. (The other 20 percent are involved in axon guidance.) In addition, 75 percent interact with each other.
"There's an aspect of gene regulation going on here that wasn't clear before," says Darnell. "Nova is acting in a complex way to change the nature of the synapse." And by changing the quality of synapse proteins, Nova may also modify synaptic plasticity—the mechanism used by repeatedly activated synapses to form memories.
Both Gouaux's and Darnell's work details synapse proteins at a specific point in time. But synapses are dynamic, releasing and recycling neurotransmitters and firing nerve impulses. In the past, neuroscientists charted these dynamics by measuring electrical activity but without visualizing individual synapses.
Now, through computer simulation, Sejnowski's group has designed an animated prediction of what happens in one particular type of synapse in the chick ciliary ganglion. They used data from three-dimensional tomography imaging—a type of electron microscopy in which a thick tissue slice is imaged at different angles to show its 3-D structure—to generate a topographic map of the synapse's crinkled surfaces. To this map, they added electrical and chemical measurements taken from wet lab experiments to simulate neurotransmission.
"It's as if we had a simulated microscope that could zoom into the synapse," says Sejnowski. The simulation program, called MCell, surprised him when it showed that most of the nerve cell transmission was occurring outside the "active zone," the area in the synapse where researchers thought most nerve transmission occurs. (For more about MCell, see this issue's Tool Box column on page 52.) "We suspect that a similar thing is happening at other synapses in the brain," says Sejnowski. He says this type of ectopic transmission may serve to increase the background activity level of neurons, sensitizing them during times of rest to be fire-ready when needed. MCell could also help drug developers "watch" the effects of candidate drugs.
Each of these three groups has added new ways to envision synapse functions. Their work shines a searchlight on new pathways to treating disorders of the central nervous system like depression, epilepsy, and movement disorders.