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Tracing behavior to the brain
A mutagenesis screen for psychiatric disease in mice
Edward R. Winstead

Survival depends on being able to sense danger and ignore much of life's background noise. In some individuals with schizophrenia, the brain's filtering mechanism breaks down, resulting in thought disturbances and psychiatric behavior. Like humans, mice that cannot ignore irrelevant stimuli behave in certain ways. By causing random genetic defects in mice and subjecting the animals to tests such as the startle response or locomotor activity test, researchers have identified several strains of mice that seem to have schizophrenia or depression. A search is underway for the genes involved.

In one of the first mutagenesis studies in mice dedicated to understanding human psychiatric disorders, researchers of the University of California in Los Angeles have screened more than 400 mice with induced mutations for psychiatric traits. The researchers have identified two strains of mice that behave like people with schizophrenia and two strains that show signs of depression. A paper describing the screening program appears in the current issue of Molecular Psychiatry.

Drosophila researchers have for decades discovered genes by inducing random changes to the insect's DNA, screening flies for abnormal behavior or signs of disease, then working backwards to identify the affected genes. The approach got a boost in the 1990s, when Joseph Takahashi, of Northwestern University in Illinois, used the strategy to create a mouse with a defective biological clock. His team of researchers later isolated the gene and characterized its function, demonstrating the potential of mutagenesis in discovering genes involved in behavior.

ENU causes hundreds of tiny changes in the genome

Genetic studies of psychiatric disorders in humans have produced widely varying results and no major genes. "Trying to identify schizophrenia genes in humans has been a complete flop," says Desmond J. Smith, of the UCLA School of Medicine. "Perhaps we can be more successful in the mouse by identifying strong behaviors and the genes involved, which will help us understand biological pathways." Smith decided to publish the paper now rather than waiting for the genes to be identified because the technique showed promise. With today's gene-hunting tools, the step of isolating the genes is relatively straightforward.

In the UCLA mutagenesis screen, researchers treat mice with a chemical called N-Ethyl-N-Nitrosourea, or ENU. The dose is sufficiently low to cause hundreds of tiny changes throughout the genome without affecting the animal's ability to reproduce. The mice are evaluated in areas such as learning, memory, fear, anxiety, and pain perception. A test for "sensorimotor gating" gauges the mouse's ability to filter out irrelevant stimuli in favor of important sensory information. Mice that score outside the norms are bred with other mice to insure that the trait of interest shows up in the next generation.

"The ENU peppers the mouse genome with 100 to 200 changes," says Smith. "But it's possible to breed out the 199 irrelevant changes, leaving the one change that's relevant to schizophrenia or some other neurobehavioral disorder."

a single-gene approach to complex disorders

Because psychiatric disease is generally thought to involve subtle changes in many genes rather than just one mutation, trying to isolate single genes in the mouse is an unproven strategy. But the strategy is increasingly winning converts in the scientific community. Large-scale mouse mutagenesis screens are underway in Europe and Israel to discover genes and create models for a variety of human conditions, according to papers in this month's issue of Nature Genetics.

"We have hit a threshold in terms of technology," says Joseph Nadeau, of Case Western Reserve University School of Medicine in Cleveland, Ohio. "Mutagenesis has been done on a small scale for 20 years, but the maturation of cloning and sequencing technologies has made a large-scale approach practical." Nadeau, who is co-author of a commentary that accompanies the papers in Nature Genetics, is exploring the possibility of an international mutagenesis program to develop mouse mutants for every gene involved in complex disorders like obesity and hypertension.

If one thinks about complex disorders as simply a collection of single-gene effects, says Nadeau, it makes sense to use mutagenesis as a way to discover the underlying genes and their functions—one gene at a time. The potential downsides of mutagenesis screening are its relative expense and the fact that some aspects of mouse biology are not relevant to humans. "There will always be irreconcilable differences, but the mouse can be used to prioritize research in humans," he says.

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Sayah, D.M., Khan, A.H., Gasperoni, T.L. & Smith, D.J. A genetic screen for novel behavioral mutations in mice. Mol Psychiatry 5, 369-377 (July 2000).
Nadeau, J.H. & Frankel, W.N. The roads from phenotypic variation to gene discovery: mutagenesis versus QTLs. Nat Gen 25, 381-384 (August 2000).

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