Professor Jean C. Shih

University Professor Jean C. Shih is internationally known for her groundbreaking studies of the brain enzyme monoamine oxidase, which is also known as MAO. MAO works by catalyzing the oxidation of a number of different neurotransmitters - the chemicals that nerve cells use to communicate - such as serotonin, dopamine, and norepinephrine. Oxidation inactivates these neurotransmitters, lowering their levels in the brain. This process can be likened to a battery being depleted of its electrical charge, and has varying effects on an individual's brain chemistry and behavior.

MAO was first isolated in 1942 and first shown to come in two forms, MAO A and MAO B, in 1962. In 1988, Shih and her collaborators were the first to have modeled the molecule's three-dimensional structure and the first to have worked out the key amino acids involved in MAO's active sites, which was critical for understanding its functions.

MAO A deals primarily with serotonin, dopamine and norepinephrine, which are essential to mood, aggression, anxiety and the sleep-waking cycle; while MAO B mainly breaks down phenylethylamine, another important mood regulator.

Shih recently received a grant of $2 million over five years from the National Institute of Mental Health to study how an individual's DNA affects their production of MAO.

An individual's genetic blueprint is embedded in the DNA sequence in the cell and then transcribed into RNA. From RNA, the information is translated into proteins that establish biological functioning in the body.

Each person has a different genetic code, which is called the MAO promoter. The genetic code is comprised of a sequence that repeats for a set number of times.

Proteins - called transcription factors - bind to the DNA sequence and allow the gene to be transcribed into RNA. From there, subsequent proteins are created that enable the body to make MAO.

"The lower the number of DNA sequence repeats, the less MAO is produced by essential proteins, said Shih. "An individual that makes more MAO has a higher incidence of depression and anxiety because the enzyme "de-activates" the beneficial properties of the neurotransmitters."

Shih and her team have discovered a novel protein - which she calls R1 - that regulates the production of MAO A. By studying this protein, they will be able to come up with new ways to inhibit the production of MAO A at the transcription level, said Shih.

"This will allow scientists to develop more efficient medications for mood and anxiety disorders," she said.

This is only the latest in a series of MAO-related discoveries achieved by Shih, who is the Boyd and Elsie Welin Professor of Molecular Pharmacology and Toxicology at the USC School of Pharmacy and holds a joint appointment with the department of cell and neurobiology at the Keck School of Medicine of USC.

Scientists who study the brain often employ the use of bioengineered mouse models, which enables them to observe neurotransmitter pathways in a living system.

For this purpose, Shih has created several strains of "knockout" mice that lacked one or of the MAO genes. She 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.

Through a renewal grant of $2.4 million for her second NIMH Merit Award, Shih is investigating the function of both MAO A & B in knockout mice.

"The MAO is knocked out in the hippocampus and frontal cortex, which are integral to brain function," said Shih. "The mice are then bred. Since the function of the brain regions is known, it is interesting to see how the brain compensates for what is missing. If you change the brain structure, then you change the developmental pattern."

A spontaneous genetic mutation in an already-bioengineered strain of mice has created what may be the ultimate model for studying behaviors such as anxiety, aggression and stress-related disorders, according to Shih.

In this current study, Shih and her colleague, Professor Kevin Chen, performed research using a strain of mice in which MAO B had been knocked out when they noticed that one of the mice was markedly more skittish.

The DNA sequence of the skittish mouse revealed that a spontaneous mutation had occurred, resulting in an MAO A/B double knockout mouse, said Shih. Shih and Chen were then able to breed this mouse and create an entire colony of MAO A/B knockout mice - the first colony to come from a spontaneous mutation.

"The availability of three different MAO knockout mice provides a unique opportunity to further examine the molecular details of the monoamine neurochemical systems associated with specific behavior or psychological states," said Shih. "It will also provide new insights for developing selective pharmacological interventions for depression, anxiety disorder and Parkinson's disease."