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Synapse Yields Up More Secrets, as Weill Cornell Team Sheds Light on Role of Key Protein

Synaptotagmin I May Be Crucial to Chemical Messaging Between Brain Cells

NEW YORK (Oct 20, 2004)

Billions of times per day, neurons in the brain use microscopic packets of neurotransmitter chemicals to pass information across the synapse — the gaps separating individual cells.

And because almost every neurological disease, addiction, and drug aimed at brain function relies on synaptic activity, advances in understanding how this messenger system works is of great importance to medical research.

Now, in a study published in the October 18 online "Early Edition" of Proceedings of the National Academy of Science (PNAS), Weill Cornell Medical College researchers believe they have identified another critical piece of the synaptic puzzle.

Research in mice suggests a protein called synaptotagmin I plays a key role in both the drop-off of messenger neurotransmitters at the surface of brain cells, as well as the pick-up and recycling of those emptied neurotransmitter packets, once that drop-off has taken place.

"Synaptotagmin I appears to have this double function. This discovery is an important new step in identifying the role different molecules play in the machinery of the synapse," explained lead researcher Dr. Timothy A. Ryan, Associate Professor of Biochemistry and Associate Professor of Biochemistry in Anesthesiology at Weill Cornell Medical College in New York City.

"It's like writing a repair manual for a car — first, you have to figure out the function of the individual engine parts. Once you know that, you can understand what's going wrong and repair it. Our ultimate goal is a kind of 'repair manual' for the synapse — and for the brain as a whole," he said.

Every human thought, action, and emotion requires rapid, complex communication between millions of neurons in the brain. To do this, packets of neurotransmitter chemicals are ferried from one brain cell to the next across the synapse. These packets — called vesicles — then bind with that cell's surface, where they discharge their cargo of neurotransmitters in a process called exocytosis.

"What you have then is an empty vesicle that needs pick-up and refilling," Dr. Ryan explained. "This pick-up involves a second process, called endocytosis."

Most types of body cells rely on this delivery/pick-up system to either take up nutrients or send out signals, but "the synapse is a specialized, 'souped-up' version of this process," Dr. Ryan explained. Over 50 years ago, scientists discovered that calcium levels on the neuron's surface were especially important to this mechanism, he said.

But which proteins in the vesicle "tune in" to these calcium levels, both in exocytosis and endocytosis?

To help find out, Dr. Ryan's lab at Weill Cornell first pioneered a new way of viewing the endocytosis-exocytosis process under the microscope.

He and co-researcher Dr. Karin Nicholson-Tomishima then focused on synaptotagmin I, a protein found within the vesicle. Previous work had already suggested that this compound is important for exocytosis.

Dr. Ryan's team compared the synaptic activity of brain cells from mice genetically engineered to lack synaptotagmin I, to those of healthy, normal mice.

They saw big differences.

"As expected, exocytosis was impaired in mice without this key protein," Dr. Ryan said. "But we also discovered that endocytosis was greatly impaired, too, upsetting the balance between the two processes. So synaptotagmin I becomes a candidate as a key coupler of both of these activities," he said.

Overall, mice without synaptotagmin I had a three-fold reduction in the rate of endocytosis compared with exocytosis, the study found.

This research follows closely on the heels of another synapse-related discovery from Dr. Ryan's lab, published last month in Nature. In that work, the Weill Cornell researchers determined that PI(4,5)P2, a lipid found on the plasma membrane of brain cells, also plays an important role in the flow of neurotransmitters across the synapse.

"These are exciting times in synaptic research," Dr. Ryan said. "We're getting closer to understanding how this important machinery works. And since so many neurological diseases and dysfunctions center on the synapse, that could mean real clinical benefits in years to come."

The study was funded by grants from the National Institutes of Health and the Hirschl Trust.

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