Building a better mouse
Robert Tindol

Some inventors hope to build a better mousetrap, but Caltech professor of biology Henry Lester’s grand goal is to build a better mouse.

Not that the everyday laboratory mouse is inappropriate for a vast variety of biological and biomedical research. But for Parkinson’s disease research, it has become clear that a strain of mutant mice with “slight” alterations would be a benefit in future medical studies. And not only would the mutant mice be useful for Parkinson’s, but also for studies of anxiety and nicotine addiction.

Though Lester and his colleagues Johannes Schwarz and Cesar Labarca have not yet produced the mouse they envision, they have already achieved encouraging results by altering the molecules that form the receptors for nicotine in the mouse’s brain. If they can just make these receptors overly sensitive in the right amount, they reason, the mice will develop Parkinson’s disease after a few months of life.

Two earlier strains of mice were not ideal, but nonetheless convinced the Lester team members they were on the right track. One strain of mice suffered from nerve-cell degeneration too quickly, developing ion channels that opened literally before birth. Their overly sensitive receptors essentially short-circuited some nerve cells. These mice usually did not survive birth, and never lived long enough to reproduce.

Another strain developed modest nerve-cell degeneration in about a year, which is a long time in a mouse’s life as well as a long time for a research project to wait for its test subjects. Lester wants the “Goldilocks mouse,” with neurons that die “not before birth—that’s too fast. Not at a year—that’s too slow and incomplete. With a mouse strain that degenerates in three months, we could generate and test hypotheses several times per year.”

Though they haven’t achieved the Goldilocks mouse yet, the strain of mice developing modest degeneration after a year is particularly interesting. Tests showed that they were quite anxious, but tended to be calmed down by minuscule doses of nicotine. For reasons not entirely understood, humans who smoke are less likely to develop Parkinson’s disease later in life, pointing to the likelihood that a mouse with hypersensitive nicotine receptors will be a good model for studying the disease.

In fact, the Lester team originally set out to build the strain of mice in order to study nicotine addiction and certain psychiatric diseases that might involve acetylcholine, a natural brain neurotransmitter that is mimicked by nicotine. The work in the past has been funded by the California Tobacco-Related Disease Research Program, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke (NINDS).

Once they had some altered mice, Schwarz (a neurologist who works with many Parkinson’s patients) realized that the dopamine-containing nerve cells were dying fastest. The death of these cells is also a cause of Parkinson’s disease. Because present mouse models for Parkinson’s research are unsatisfactory, the researchers applied for, and soon received, funding from the National Parkinson Foundation, Inc. (NPF).

Not only did the researchers receive the NPF funding, but they also were named recipients of the Richard E. Heikkila Research Scholar Award, which is presented for new directions in Parkinson’s research. “The Heikkila award is gratifying recognition for our new attempts to develop research at the intersection of clinical neuroscience and molecular neuroscience here at Caltech,” says Lester.
Dr. Yuan Liu, program director at NINDS, says the Lester team’s research is important not only because it is the first genetic manipulation of an ion channel that might lead to a mammalian model for Parkinson’s disease, but also because the research is a pioneering effort in an emerging field called “channelopathy.”

“Channelopathy addresses defects in ion channel function that causes diseases,” Liu says. “Dr. Lester is one of the pioneers working in this field. We’re excited about this development, because Parkinson’s is a disease that affects such a large number of people—500,000 in the United States. The research on Parkinson’s is one of the research highlights that the NINDS is addressing.”
The first results of the Lester team’s research are reported in the February 27 issue of the journal Proceedings of the National Academy of Sciences (PNAS). In addition to Labarca, a member of the professional staff in Caltech’s department of biology, and Schwarz, a visiting associate, the collaborators include groups led by professors James Boulter of UCLA and Jeanne Wehner of the University of Colorado.
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