Spontaneous mutation produces new MAO A/B knockout mouse

A combination of luck and scientific curiosity has produced a mouse lacking two isoenzymes, MAO A and MAO B, that have been linked to violent criminal behavior and Parkinson’s disease. The MAO A/B knockout mouse should provide an excellent model in which to address the specific roles of these neurotransmitters and their receptors in anxiety and stress-related disorders.

The research appears as the “Paper of the Week” in the September 17 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

The monoamine oxidase isoenzymes MAO A and MAO B are involved in breaking down neurotransmitters. Higher or lower than normal amounts of these isoenzymes result in irregular neurotransmitter levels, causing abnormal behavior. Realizing the connection between neurotransmitter levels and behavior, psychiatrists routinely use MAO A inhibitors as antidepressants and MAO B inhibitors for Parkinson’s disease.

By making knockout mice lacking either MAO A or MAO B, Jean C. Shih, a Professor at the University of Southern California School of Pharmacy, and her collaborators previously showed how each isoenzyme functions in the body. However, up until now, scientists have been unsuccessful at making a mouse lacking both MAO A and MAO B.

This all changed when Dr. Shih and her colleague, Professor Kevin Chen, noticed that one of the mice in an MAO B knockout litter was a little different from its littermates–it had a lower body weight and was extremely hyper-reactive when approached. Wanting to figure out why the mouse was different, the scientists decided to breed the mouse and examine its offspring.

The scientists discovered that the mice not only had high levels of neurotransmitters broken down by MAO B, as would be expected in mice lacking MAO B, but also had high levels of neurotransmitters broken down by MAO A. This indicated that somehow the MAO B knockout mouse had also lost its ability to produce MAO A.

“Both MAO A and MAO B are critically important,” says Dr. Shih. “When both are missing in mice, brain neurotransmitters levels increase greatly and body weights are smaller. The mice also show anxiety and aggressive behavior, especially under stress.”

Looking further into the matter, Dr. Shih determined that a spontaneous mutation in a single nucleic acid base pair in the MAO A gene created a premature stop which prevented it from being made into a protein. The scientists hypothesize that the mutation was due to elevated levels of the MAO B substrate phenylethylamine in the MAO B knockout mice. Phenylethylamine is a neuromodulator which, when broken down into its metabolites, has been shown to cause mutations in DNA.

“Interestingly,” says Dr. Shih, “a similar single base pair mutation occurs in the MAO A gene in the men of a Dutch family who show impulsivity and aggressive behavior.” This mutation in the Dutch family’s MAO A also produces a premature stop codon which prevents production of the protein.

Dr. Shih’s MAO A/B knockout mice should provide scientists with good model in which to study the combined actions of MAO A and MAO B, as well as examine the roles of neurotransmitters in anxiety- and stress-related disorders.