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Yale-Weill Cornell Collaboration Uncovers Secrets of the Synapse

New Clues to How Messages Are Passed Between Brain Cells Could Speed Research into Neurological Disease, Drug Abuse

NEW YORK (Sep 21, 2004)

As you read this, billions of synapses lying between the cells of your brain are using complex chemical signals to pass information from one neuron to the next.

It's a process crucial to healthy brain function as well as drug development, drug addiction and neurological disease, and researchers at Yale University School of Medicine-Howard Hughes Medical Institute and Weill Cornell Medical College believe they now have a better understanding of how synaptic transmission works.

Their findings, to be published in the September 23 issue of Nature, focus on the role of a lipid found on the plasma membrane of brain cells, called PI(4,5)P2. In the absence of a sufficient supply of that lipid, synaptic transmission slows, and with it, neurological function.

"The role of PI(4,5)P2 in synaptic transmission had been inferred by previous studies, but this is the first study to provide conclusive genetic demonstration that lowered PI(4,5)P2 production at synapses impairs the efficiency of neurotransmission," said Dr. Pietro De Camilli, Eugene Higgins Professor of Cell Biology and Howard Hughes Medical Institute Investigator at the Yale University School of Medicine.

"Since the synapse is so important for everything we do, and every neurological medicine or drug of abuse works on the synapse, it's quite likely that defects in this process will rear their head as neurological disease of some kind," explained researcher Dr. Timothy A. Ryan, Associate Professor of Biochemistry at Weill Cornell Medical College in New York City and a co-author of the study.

Here's how it works: Within brain cells, information is stored as electrical signals. However, before that information can be passed cell-to-cell, it must first be converted at the cell's surface into chemical signals that flow via the synapse.

Each synaptic transmission involves the carriage of a packet, or "vesicle," of neurotransmitter chemicals. Each synapse has only on the order of a 100 of these packets.

"In the meantime, however, each synapse is firing away about 20 times per second," Dr. Ryan said. At that rate, vesicles would be depleted too early, ending transmission.

Luckily for our brains, a constant recycling of these packets occurs. As neurotransmitter vesicles are dropped off and used up on the cell surface, like milk being delivered on a doorstep, "the synapse has to come up with a way to know when to collect the empties," Dr. Ryan explained.

That's where the PI(4,5)P2 lipid, a key component in the cell's plasma membrane, comes in. Based on previous work led by the study's senior author Dr. Pietro De Camilli, the investigators suspected that chemical changes in PI(4,5)P2 were a "signal" that empty vesicles were ready for pick-up, recycling, and re-use.

To test that theory, Dr. De Camilli's team engineered special "knockout" mice bred without a gene encoding a kinase (a kind of protein) called PIPK1. "You need this kinase to synthesize the PI(4,5)P2 lipid," Dr. Ryan explained.

Mouse pups without this gene were born apparently normal, but could not feed, and soon died. The Yale researchers then sent the mice to Dr. Ryan's lab at Weill Cornell for closer examination of nerve tissue under the microscope.

"My lab specializes in studying this vesicle cycle," he said. "We compared synapses from the brain tissue of genetically altered mice with those of normal mice."

The result? Synapses without PIPK1 kinase recycled vesicles "about 2 times slower than normal," Dr. Ryan said.

"That means they run out of gas, and it takes them longer to recover. That's a major defect."

"At the molecular level, it's telling us that you need this kinase-lipid connection whenever neurotransmitter vesicles are delivered to the cell surface. This chemical relationship seems to mark the cell surface, sending out a 'come-get-me' signal. It's a chemical flag that's crucial to the process."

The fact that mice lacking this kinase-lipid activity had poorly developed nervous systems and died soon after birth highlights the importance of PI(4,5)P2 lipid signaling in proper neurological function, he said.

"It really brings us to a deeper understanding of the daily life of the synapse," he added. "While it's too early to point to PI(4,5)P2 dysfunction as key to any particular condition or disease, these findings have brought us a much closer understanding of how this important process works."

The study was funded by grants from the National Institutes of Health, the Yale Center for Genomics and Proteomics, and the Howard Hughes Medical Institute.

Besides Drs. De Camilli and Ryan, co-researchers included Howard S. Moskowitz, also of Weill Cornell Medical College, New York City; Dr. Gilbert Di Paolo, Keith Gipson, Dr. Markus R. Wenk, Dr. Sergey Voronov, Masanori Obayashi, Dr. Reiko M. Fitzsimonds — all of Yale University School of Medicine, New Haven, Conn.; and Dr. Richard Flavell, also of Yale and an Investigator at the Howard Hughes Medical Institute.

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