The absence of a key signaling protein in the brain during infancy could lead to anxiety disorders later in life, scientists say. According to findings published today in the journal Nature, mice lacking the receptor protein for the chemical messenger serotonin just after birth exhibit abnormal anxiety as adults.
Researchers have known for some time that mice genetically engineered to lack the receptor for serotonin, a neurotransmitter, show anxiety-like behavior. But the new results go one step further, revealing when in life and where in the brain the link between serotonin receptors and anxiety behavior is forged. As in earlier studies, the investigators, led by Ren¿ Hen of Columbia University, first created a line of so-called knockout mice that lacked the gene encoding the receptor protein. Those mice showed the expected signs of anxiety, such as moving around less open spaces and taking longer to start eating in new environments as compared with normal animals. To determine which of the two receptor populations--the one in the forebrain or the one in the brainstem--is most critical in that regard, the team then crossed the knockout mice with a line engineered to activate receptor expression in particular brain regions. The resulting line of double-transgenic "rescue" animals expressed the serotonin receptors only in the forebrain, but exhibited normal anxiety behavior. Further tests, in which the drug doxycycline was used to suppress the receptors in mice at various stages of development, showed that eliminating the receptors in juvenile or adult mice did not elicit over-anxiousness.
"Forebrain serotonin receptors are needed during the development of newborns to modulate the predisposition to anxiety-like behavior, but are no longer critical during adult life," Solomon Snyder of Johns Hopkins University explains in a commentary accompanying the report. He proposes that variations in serotonin-sensitive neurons and serotonin receptors early in life might account for the importance of maternal nurturing in preventing emotional disorders later in life. Rats that were not groomed sufficiently as pups by their mothers display elevated levels of anxiety as adults, he notes. "Assuming that we can equate developmental stages in mice and humans," Snyder reflects, "these findings might be relevant to brain development and the genesis of anxiety in people too."