Weill Cornell researchers solve a 30-year puzzle of nerve cell function

By Jonathan Weil

Weill Cornell Medical College researchers have shed light on the function of the synapse -- the gap between nerve cells where information is passed from one cell to the next. In the process, they have solved a 30-year puzzle on how exactly nerve cells transmit signals.

The finding could one day help determine what goes wrong in ailments like Alzheimer's disease and epilepsy, said Dr. Timothy Ryan, associate professor of biochemistry.

"Almost every single drug that you take in the nervous system works in the synapse -- it's pivotal," said Ryan. "The synapse is key in terms of information flow in the brain, so almost certainly there are many diseases that are the result of the dysfunction in this connection."

In the new study, published in latest issue of the journal Neuron, Ryan and Tomas Fernandez-Alfonso, a graduate student in the Weill Cornell Neuroscience Program, looked specifically at conditions inside nerve endings while signals are being transmitted.

Although messages are transmitted electrically inside the nerve, the signal is translated into a chemical signal when the message jumps across the synapse from one cell to the next.

"What a neuron does for a living is basically to transfer information," said Ryan. "In the same way phone lines in your house are electrical -- but the energy is transferred into an acoustic signal so you can hear it -- 99 percent of cells in the brain have to convert that electrical signal to a chemical signal, and the synapse is a little machine that does this conversion."

The chemical signal is known as a neurotransmitter -- in the brain, this is most often glutamate -- which is packaged inside tiny packets called vesicles. When the nerve cell is fired, it dumps the neurotransmitter at the synapse, and then the vesicle is re-formed and refilled. But because each synapse contains only about 100 vesicles, sustained stimulation of the cell would cause the vesicles to be depleted too quickly. Early studies suggested that it would take about one minute to re-form vesicles once they are all depleted.

The problem is that a minute might as well be eons in terms of nerve-cell firing, which operates on a split-second timetable.

"Say you are contracting your toes because you are walking or dancing around the room -- you could have 10 to 30 signals per second, and you'll use these guys up really quickly," said Ryan. "In the brain, it could be even more rapid. The brain is not sluggish. You are getting signals frequently -- easily 10 to 20 times a second."

While new vesicles can be made in the cell's body and transferred to the tips, or processes, this could be a distance of almost two feet for some nerves in the body. For example, cells that move muscles in the toes can extend from the cell's body located in the base of the spinal cord -- far too long for the rapid transfer of vesicles.

"The vesicle dumps its contents and you have 99 left, but you are going to get another 99 stimuli long before you get any vesicles from the cell body," said Ryan.

In the new study, the researchers looked at rat brain cells grown in the laboratory. They added a gene to the cells that produced a fluorescent protein inside the vesicles that could be picked up by optical equipment, and that allowed them to look at the supply and demand problem for vesicles directly.

They found that vesicles can be re-formed relatively rapidly -- taking about one second -- but that the mechanism can only re-form one vesicle at a time. Earlier studies suggested a depletion of all vesicles at once in up to a minute under experimental conditions. But that rarely happens in real life, said Ryan.

"This is sort of like a build-up of garbage cans on a sidewalk during a strike. When the strike is over, it can take all day to clear up all the garbage cans, but normally the guys take one garbage can at a time and it's fine."

Even in those rare cases where all the vesicles are depleted at once, the relatively slow re-forming time could help keep the system from being overloaded.

"There is a property of synapses, called depression, where cells fail to continue to respond faithfully to commands," Ryan said. "Probably the brain has evolved a way to make use of depression to sort of protect itself from too much information and prevent overloading on the receiving end of the synapse."

The study was funded by the National Institutes of Health and the Irma T. Hirschl Trust.