That electric feeling  pg. 6

Most children with ADHD have normal thyroid function. But when the mutated version of the human gene that causes RTH is inserted into mice, the resulting “transgenic” animals exhibit the hallmark characteristics of ADHD – hyperactivity, impulsivity and difficulty paying attention.

“The hyperactivity dissipates when they get into adulthood, but the attentional deficits and impulsive behavior persist,” says McDonald, who has continued to study these “transgenic” mice since moving his lab to Vanderbilt in 1999. Males are more likely than females to exhibit these symptoms. In addition, methylphenidate dampens their hyperactivity, whereas the drug spurs more activity in normal control mice.

This mouse model, which displays many characteristics of the human condition, may be useful in testing new drugs to treat the disorder. It also may help explain how environmental factors – including exposure to hormones -- can contribute to the development of ADHD, says McDonald, who is assistant professor of Pharmacology and director of the Murine Neurobehavioral Laboratory.

As pups, the transgenic mice have a mild "thyroid resistance phenotype," characterized by high levels of thyroid stimulating hormone and high thyroid hormones, which also are seen in the human condition (RTH). This lasts for only three or four weeks, however. By the time the mice exhibit ADHD-like behaviors, their hormone levels are completely normal. "We think it's the elevated thyroid hormones (during development) that are causing the long-term brain and behavioral abnormalities," he says.

The tender brain

“The thyroid hormone is critically important for brain development, and regulates hundreds of genes,” McDonald continues. “What these mice show us is that it’s possible to have a transient thyroid abnormality during development, and later on to have many of the symptoms associated with ADHD.”

In McDonald’s studies, normal pups born to transgenic mothers have transient hyperactivity, suggesting that exposure to excess maternal thyroid hormones in the womb also can contribute to ADHD. “My suspicion is that transient thyroid abnormalities during development contribute to a lot more cases of ADHD than we’re currently aware of,” he says.

McDonald and his colleagues are using gene microarrays, plates containing thousands of different pieces of genetic sequences, to search for the expression of genes during different periods of development in the mouse that may be associated with the RTH mutation. Not long ago, it might have taken years to determine the impact of a single gene. Today, the Vanderbilt researchers can screen 23,000 genetic sequences simultaneously.

The thyroid connection to ADHD also raises questions about the role of pollutants. In particular, exposure to PCBs through breast milk or in the womb has been linked to problems with learning, memory and attention.

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