ScienceDaily (May 15, 2012) A novel mechanism for anxiety behaviors, including a previously unrecognized inhibitory brain signal, may inspire new strategies for treating psychiatric disorders, University of Chicago researchers report.

By testing the controversial role of a gene called Glo1 in anxiety, scientists uncovered a new inhibitory factor in the brain: the metabolic by-product methylglyoxal. The system offers a tantalizing new target for drugs designed to treat conditions such as anxiety disorder, epilepsy, and sleep disorders.

The study, published in the Journal of Clinical Investigation, found that animals with multiple copies of the Glo1 gene were more likely to exhibit anxiety-like behavior in laboratory tests. Further experiments showed that Glo1 increased anxiety-like behavior by lowering levels of methylglyoxal (MG). Conversely, inhibiting Glo1 or raising MG levels reduced anxiety behaviors.

"Animals transgenic for Glo1 had different levels of anxiety-like behavior, and more copies made them more anxious," said Abraham Palmer, PhD, assistant professor of human genetics at the University of Chicago Medicine and senior author of the study. "We showed that Glo1 was causally related to anxiety-like behavior, rather than merely correlated."

In 2005, a comparison of different mouse strains found a link between anxiety-like behaviors and Glo1, the gene encoding the metabolic enzyme glyoxylase 1. However, subsequent studies questioned the link, and the lack of an obvious connection between glyoxylase 1 and brain function or behavior made some scientists skeptical.

"When people discover a gene, they're always most comfortable when they discover something they already knew," Palmer said. "The alarming thing here was there was a discovery of something that nobody knew, and therefore it seemed less likely to actually be correct."

A 2009 study from Palmer's laboratory suggested that differences in Glo1 expression between mouse strains were due to copy number variants, where the segment of the genome containing the gene is repeated multiple times. To test this hypothesis, lead author Margaret Distler inserted two, eight or ten copies of the Glo1 gene into mouse lines. She then ran experiments such as the open field test, in which researchers measure how much time a mouse spends in the center of an arena versus along the walls, to detect changes in anxiety behavior.

The results confirmed a causative role for Glo1 copy number variants, as mice with more copies of the Glo1 gene exhibited higher anxiety-like behavior in their experiments.

"It's the first study to show that it's the copy number variant that has the potential to change Glo1 expression and behavior," said Distler, an MD/PhD student in the Pritzker School of Medicine's Medical Scientist Training Program. "Our study was a physiological representation of what it means to increase Glo1 expression for anxiety."

The researchers then set about answering the mystery of how Glo1 expression influences anxiety-like behaviors. The primary function of glyoxylase 1 is to metabolize and lower cellular levels of methylglyoxal, a waste product of glycolysis. Distler produced the opposite effect by injecting MG to artificially increase its levels in the brain, finding that raising MG levels quickly reduced anxiety symptoms in mice.

Original post:
Mystery gene reveals new mechanism for anxiety disorders

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