Investigators decipher neuron signaling
Dr. Louis DeFelice (right) and Aurelio Galli, Ph.D., are exploring how neurons communicate. (Photo by Donna Jones Bailey)
Vanderbilt University Medical Center investigators have discovered a previously unknown mechanism that enables neurons to quickly send signals back and forth.
The new model, published recently in the Proceedings of the National Academy of Sciences, details how the brain's neurotransmitters ‹ the vehicles by which neurons communicate ‹ are able to leave their own neuron, traverse the synaptic cleft to stimulate another neuron, then quickly return to be taken up by the 'sender.'
Discovery of the new transport model could lead to advances in the investigation and design of drugs ‹ such as antidepressants ‹ that work by blocking neurotransmitter re-uptake in the brain. The new model could also lead to possible treatment advances for drugs of abuse like cocaine, researchers said.
"We have been targeting these transporter molecules for a long time without knowing how they work," said Dr. Louis J. DeFelice, professor of Pharmacology. "Now that we know how these drugs work there are many possibilities in terms of designing new drugs with fewer side effects."
Neurotransmitters are what neurons use to talk to each other. For example, if neuron A wanted to send a signal to neuron B it would fire a stream of neurotransmitter, for example serotonin, at neuron B. Once these serotonin molecules stimulate neuron B, they have to be taken back up, metabolized, or diffused away into the surrounding membrane.
In the previous model, the transporters, which are located in neuron A, would carry the neurotransmitters like a backpack and deliver them one at a time back into the inside of neuron A.
"I don't have to tell you that that would take forever in a molecular sense. The neurotransmitters simply can't be out there that long tickling the surface of neuron B. Our brains need to respond quickly, and recover to be ready to respond again. There has to be a method of taking neurotransmitters back up more quickly than one at a time." said DeFelice.
The model DeFelice's lab discovered shows transporter molecules act less like a carrier ‹ picking up neurotransmitters one at a time ‹ and instead form a sort of hole that accepts and admits vast numbers of a particular neurotransmitter. In other words, these molecules are acting like 'channels.'
"One important thing to appreciate is that the concentration of molecules in the synaptic cleft is very high for a short period of time. So there is a very large concentration of neurotransmitters to be removed in milliseconds," said DeFelice.
Once the neurotransmitters are brought into the neuron by these transporter molecules, they are repackaged and released again later to again signal the next neuron.
It is important to have a basic understanding of how neurons communicate. On this basis we can understand normal function, a first step in understanding the complexity of the mind, mental health and issues like addiction.
"Of the commonly prescribed antidepressants, one of them acts on the transporter molecule for norepinephrine. Drugs that are abused, like cocaine, also act on these transporters," said DeFelice.
When drugs interfere with re-uptake, neurotransmitters become 'stuck' and continue to stimulate the neuron. These loose neurotransmitters are then metabolized by the surrounding tissues or are diffused into areas in which they are not normally present.
"All types of drugs that work on transport molecules for neurotransmitters have this same effect: increasing the concentration and duration of the neurotransmitter (such as serotonin or norepinephrine) in the synaptic cleft, the communicating space between neurons. The concentration of these neurotransmitters gives all sorts of extra signals to the brain, leading to both the beneficial ‹ and disastrous ‹ effects," said DeFelice.
This new understanding of neurotransmitter transport is allowing researchers to examine the long-term results of exposure to drugs that affect transporter molecules function.
It is hoped that once a better understanding of how drugs affect transporter molecules is established, scientists can design both better antidepressants and medications that will act as surrogates for drugs of abuse.