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Anxiety Tied to Missing Serotonin in Infancy

Mouse study suggests function during development is crucial

WEDNESDAY, March 27, 2002 (HealthDayNews) -- The absence of a serotonin receptor during infancy could lead to anxiety in adulthood.

A new study reports that mice genetically altered to lack serotonin1A receptors in their forebrain during a critical window of development just after birth displayed anxious behaviors in later life -- even if the receptor was activated at a later stage in life.

According to the researchers, the findings suggest that the activity of the serotonin receptor is crucial not only in a certain region of the brain, but also during a specific period of growth and development. The study appears in the tomorrow's issue of Nature.

The researchers, led by René Hen, an associate professor at the Center for Neurobiology and Behavior at Columbia University in New York City, were looking into the brain chemistry involved in emotion.

Serotonin is a chemical that serves as a neurotransmitter, which helps brain cells communicate. Serotonin levels have been implicated in anxiety, depression, migraine headaches, and many other ailments.

Because many of the drugs used to treat mood and anxiety disorders target the serotonin system, Hen and his colleagues decided to use genetic knockout techniques to study the serotonin1A receptor.

First, the team created mice in which the function of the serotonin 1A receptor was absent in different regions of the brain. Then they tested the response of the animals to an elevated maze with two uncovered platforms. It is known that in anxious animals, the fear of the elevated areas and the open platforms overwhelms natural curiosity, and they spend far less time in those areas.

The first portion of the study revealed that as long as the serotonin1A receptor was functional in the hippocampus and cortex, the mice didn't develop anxious behavior in later life.

In the second portion of the study, the researchers examined whether the function of the receptor during a specific period of development was important.

The team genetically engineered mice so that feeding them a diet laced with the antibiotic doxycycline when they were 10-to-12-weeks old would switch off the function of the serotonin1A receptor.

The doxycycline diet wiped out the rodents' serotonin1A receptors as adults, but didn't lead to anxious behavior in the maze.

But when they administered doxycycline to the animals while still in the womb, it eliminated the animals' serotonin1A receptors in the forebrain as newborns, and resulted in severe anxious behavior.

"There is a particular period in the postnatal development when receptor expression is critical for brain development to take place in such a way that the mice are normal as adults," says Hen. "If the receptor is absent during that period, you get a whole cascade of events in brain maturation." He adds, however, that the exact mechanisms are not yet clear.

"It's a window when the receptor is not expressed right after birth," says Dr. Miklos Toth, an associate professor of pharmacology at Cornell University's Weill Medical College in New York. "When the receptor is missing at that particular [time], it will have consequences in later life, which is anxiety in the mouse."

"The bad news is that when things happen, nobody knows that they've happened," Toth continues. If the same mechanism holds for humans, then bad things can happen during early childhood without showing any problems early. "By the time the child is grown up, it's too late to causatively influence it," he says. "Every therapy that we have is actually just trying to balance whatever happened there."

On the other hand, says Toth, if researchers learn how to recognize when the serotonin system gets out of balance at an early age or during pregnancy, doctors could test for the problem using genetic means.

He says that these findings could also help identify which brain circuits are crucial for antidepressants to do their work. "Having access to mechanisms that are important in the action of antidepressants may lead to the development of new antidepressants," says Hen.

What To Do

This Scientific American "Ask the Expert" column looks at whether fear is genetic.

You can find out more about anxiety from the Anxiety Disorders Association of America or the National Institute of Mental Health.

SOURCES: René Hen, Ph.D., associate professor, Center for Neurobiology and Behavior, Columbia University, New York City; Miklos Toth, M.D., Ph.D., associate professor, Department of Pharmacology, Weill Medical College, Cornell University, New York City; March 28, 2002, Nature
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