Frog science helps to explain how the environment may have permanent effects on the nervous system

Scientists studying how the nervous system develops in frogs have found that altering the pattern of electrical signaling in individual neurons changes the kinds of neurotransmitters they produce.

While preliminary, the finding may lead to a new understanding of how epilepsy and other neurological disorders develop and may even point to new ways of preventing or treating these disorders.

Many neurological and mental disorders result from problems with neurotransmitters (nerve-signaling chemicals). Some of these chemicals, called excitatory neurotransmitters, increase the amount of activity in the nervous system, while others, called inhibitory neurotransmitters, decrease the amount of activity. Previous studies have shown that environmental signals can cause some neurons to change the neurotransmitters they express, but researchers thought this phenomenon was restricted to just a few kinds of neurons under limited circumstances. The new study shows that the phenomenon is widespread, at least in frogs, and that factors influencing electrical activity in individual neurons can play a role in fine-tuning the functions of many neurons in the nervous system. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the June 3, 2004, issue of Nature.1

"The data suggest that the type of neurotransmitter produced results from a partnership between genetic regulation and electrical activity," says senior author Nicholas C. Spitzer, Ph.D., of the University of California, San Diego. "This allows more flexibility than genes alone, but it is a two-edged sword - the system can also be perturbed more easily. If we can turn the edges of the sword to our advantage, we may be able to help the nervous system heal itself."

The researchers studied the developing spinal cord in frog embryos. In one set of embryos, they genetically manipulated properties of the cell membranes in order to increase or decrease the neurons' electrical activity. In other embryos, they did the same thing using drugs.

Increasing the amount of electrical activity in the neurons increased the number that produced inhibitory neurotransmitters, the researchers found. Lowering the amount of activity in the neurons increased the production of excitatory neurotransmitters. In both cases, the changes seemed to be an attempt by the nervous system to regain a balance between excitatory and inhibitory signals.

By looking at cells in a culture dish, the researchers found that increasing or decreasing electrical activity for as little as 5 hours was enough to cause the changes they observed. Altering the neurons' activity later did not reverse the effect. This suggests that there are critical periods for these changes during development, the researchers say.

Usually when the nervous system adapts to drugs or other stimuli, it does so by changing the neurotransmitter receptors on nerve cells, says Gabrielle Leblanc, Ph.D., a program director at NINDS. This study shows that neurons also can change the neurotransmitters themselves. "It helps to explain how the environment may have permanent effects on the nervous system," Dr. Leblanc says. This information might help researchers understand how epilepsy, depression, and other disorders develop. It may also lead to new understanding about how drugs used to treat neurological disorders might cause long-term changes in the nervous system, she adds.

While the results are intriguing, this study looked only at how spinal cord signaling develops in embryonic frogs. The researchers don't know yet if similar changes might be at work in the brain, or whether they occur in adult animals and/or in humans. More studies are needed to answer these questions.

If researchers can learn how to control the neurotransmitter changes in people, they might be able to find better treatments for human diseases, Dr. Spitzer says. "If we understand how the car works, then we can fix it."

Dr. Spitzer and his colleagues are now planning follow-up studies to identify the mechanisms that cause the nervous system to regain equilibrium. It may be necessary to control these mechanisms in order for therapies that alter neuronal activity to be effective. They are also planning studies to see if other kinds of neurotransmitters are regulated in the same way as the ones examined in this study.

The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation's primary supporter of biomedical research on the brain and nervous system.