Researchers reverse learning problems in mice with gene disorder

A common cholesterol-lowering drug appears to reverse learning and attention deficits in mice with neurofibromatosis type 1 (NF1). Alcino Silva and colleagues, who announced the discovery, say their finding is "exciting from a clinical perspective," both because it will benefit NF1 patients and because the treatment may also help individuals with other forms of learning disabilities.

NF1 is a disorder in which tumors grow on nerves throughout the body. The condition affects approximately one million people worldwide, with about half of them exhibiting deficits in attention, motor coordination, and the ability to learn new information. Additional effects can include behavioral and emotional problems. The genetic disorder is caused by the overactivity of Ras, a protein that regulates cell growth and proliferation. Excess Ras activity also inhibits long-term potentiation, which is the basis for remembering learned information.

Silva, whose team first linked NF1-associated learning disabilities to overactive Ras, realized that the statin drugs routinely used to lower cholesterol could affect Ras levels as well. Statin drugs lower cholesterol by blocking the effects of certain fats-and because these same fats are needed by Ras, statin drugs lead to reduced Ras activity.

Silva and colleagues administered the statin drug lovastatin to mice bred with the NF1 mutation. These mice exhibit learning disabilities, attention problems, and coordination deficits similar to those seen in humans with NF1. The researchers then compared the mice to NF1 mice receiving a placebo, using three tests measuring attention, spatial learning, and coordination. They report that lovastatin treatment "reversed [the mice's] spatial learning and attention impairments," actually leading to better performance on two of the tests than that seen in normal mice.

Because lovastatin is already approved for use in humans, three clinical trials are already underway to determine if the drug will have similar effects on children or adults with NF1. In addition, Silva and colleagues believe lovastatin may prove to be an effective treatment for other groups of learning disabled individuals. "The Ras pathway is central to memory and learning," says Silva, "and I believe Ras is connected to either the problem or the solution in many other learning disabilities, directly or indirectly."

Editor's note: A different research group announced recently that in fruit flies, a substance called MPEP appears to reverse behavioral problems associated with Fragile X syndrome, another common genetic cause of behavior and learning problems. Such findings show the tremendous potential that gene research holds for understanding and treating learning and behavior problems once thought to be untreatable.

"The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1," W. Li, Y. Cui, S. A. Kushner, R. A. Brown, J. D. Jentsch, P. W. Frankland, T. D. Cannon, and A. J. Silva, Current Biology, Vol. 15, No. 21, November 8, 2005, 1961-7. Address: Alcino Silva, Department of Neurobiology, University of California at Los Angeles, Los Angeles, CA 90095.

"Recreating 'Flowers for Algernon' with a happy ending," news release, University of California Los Angeles, November 7, 2005.

"Common drug cures learning disability," Gaia Vince, New Scientist, November 7, 2005.