A spontaneous mutation in a strain of mice has created what may be the ultimate model for studying behaviors such as anxiety, aggression and stress-related disorders, according to researchers from the USC School of Pharmacy and the Keck School of Medicine of USC.
The mutation, the brain chemistry and the behavioral changes it produces are detailed in a recent issue of the Journal of Biological Chemistry, which named it Paper of the Week for its significance and overall importance.
Jean C. Shih, the Boyd and Elsie Welin Professor of Molecular Pharmacology and Toxicology in the USC School of Pharmacy and principal investigator on this study, is internationally known for groundbreaking studies of the brain enzyme monoamine oxidase.
Monoamine oxidase, or MAO, appears to work by bringing about the oxidation of various neurotransmitters such as serotonin, dopamine and noradrenaline.
Oxidation inactivates these neurotransmitters, lowering their levels in the brain. The process has varying effects on brain chemistry, and thus behavior.
In past studies, Shih has shown that mice in whom the MAO A enzyme is inactivated tend to become unusually aggressive – a finding that has been bolstered by observations that humans with changes in their levels of MAO A are prone to violent, criminal or impulsive behavior.
In the current study, Shih and colleague Kevin Chen performed research using an already bioengineered strain of mice in which the other type of MAO – MAO B – had been knocked out. But they noticed that one of the mice was different from their single knockout brethren, said Shih who also holds the title University Professor.
It was of “markedly lower body weight,” she noted, and “exhibited extreme behavioral hyperactivity triggered by the approach of the experimenter to the animal’s cage, which resulted in an exaggerated escape response.
“This behavior – which looked a lot like what is termed anxiety or panic in humans – had not been seen in the “normal” MAO B knockout mice before,” Shih said. The DNA sequence of the skittish mouse revealed the spontaneous mutation in one single DNA base pair in the MAO A gene, as well as the already deficient MAO B gene, resulting in an MAO A/B double knockout mouse, Shih said.
Shih and Chen were then able to breed this mouse and create an entire colony of MAO A/B knockout mice.
“Unfortunately, MAOA/B knockout mice cannot be generated through the breeding of MAO A knockout and MAO B knockout mice, due to the close proximity of the isoenzyme genes on the X-chromosomes,” Shih said.
“We are very excited to have inadvertently obtained MAO A/B double knockout mice, which is essential for our studies,” she said.
The spontaneous mutation in the single base pair of DNA is similar to the one found in males in a Dutch family who are deficient in MAO A and have exhibited impulsive and aggressive behavior, said researchers.
The MAO A/B knockout mice are unique in their brain chemistry and behavioral traits.
According to Shih, they show a number of anxiety-related behaviors, such as being afraid to explore a new territory, freezing in place when put in an elevated maze and chasing – then quickly fleeing – when a new mouse was put into their cage.
“Chases were extremely rapid,” the researchers noted, “and would terminate either by brief physical aggressive contact, or on occasion, by animals jumping against the cage walls.”
“We have learned that the monoamine neurotransmitter pathways regulate several behaviors including anxiety, aggression and stress-related disorders,” Shih said.
“Furthermore, a different magnitude of change in these neurotransmitters will show different types of behavior.”
The availability of three different MAO knockout mice provides a unique opportunity to examine the molecular details of the monoamine neurochemical systems associated with specific behavior or psychological states, said researchers.
A MERIT Award from the National Institute of Mental Health supported the work.
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