A commonly prescribed drug reverses learning and attention deficits in a mouse model of the genetic disorder Neurofibromatosis type I

November 07, 2005

This week, researchers report evidence that a statin drug already shown to be safe for use in humans has proven effective at correcting cell-cell communication and curing learning disfunction in a mouse model of Neurofibromatosis type I, a human genetic disorder that causes learning disabilities in millions of people worldwide.

Learning disabilities affect 5% of the world's population, have a profound impact on countless lives, and cost billions of dollars, but there is little or nothing that we are currently able do to prevent or treat this enormous problem. At the heart of this challenge is our lack of understanding of the mechanisms underlying this complex class of brain problems. In an effort to understand these disorders and develop treatments, Dr. Alcino Silva and colleagues at UCLA have focused research on the study of the most common genetic cause for learning disabilities: Neurofibromatosis type I (NF1). The idea behind the NF1 research is that if we understand this particular learning disability, which is caused by a single defective gene, and manage to develop effective and sustainable treatments, we may be able to use the information learned to tackle this general class of learning and memory problems.

Because of the difficulties and limitations of studying mechanisms of memory in human patients, the researchers decided to study NF1 in mice. The scientists had previously shown that mice with the mutations that cause NF1 in human patients possess many of the features of this complex disorder, including deficits in spatial learning, attention, and motor coordination. Studies of these mutant mice showed that the learning deficits are caused by the overactivity of a molecule called Ras, causing an imbalance between signals that activate brain cells and those that inhibit them, and leading to deficits in cell-cell communication needed for learning.

The work reported by Silva and colleagues this week in Current Biology demonstrates that a commonly prescribed statin drug, Lovastatin, can reverse the overactivity of Ras, decrease inhibition, repair the cell-cell communication deficits, and cure the learning disabilities of the adult Nf1 mutant mice. These findings are tremendously exciting because they suggest that the disabling learning deficits associated with NF1, a disorder that affects one in three thousand people world-wide, could be cured with a class of relatively safe drugs (statins) that millions of people have taken for extended periods of time in the last 20 years. Importantly, the findings also demonstrate that contrary to popular belief, the cognitive deficits associated with this disorder are not irreversible developmental deficits, since a limited treatment in adult mice can effectively reverse this condition. Because the mechanisms of NF1 function are similar in mice and men, these findings suggest that statins will be an effective strategy to treat NF1 in humans.
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The researchers included Weidong Li, Yijun Cui, Steven A. Kushner, Robert A.M. Brown, J. David Jentsch, Paul W. Frankland, Tyrone D. Cannon, and Alcino J. Silva of the University of California, Los Angeles in Los Angeles, California. This study was funded by grants from the NIH (R01 NS38480), Neurofibromatosis, Inc. (National, Illinois, Mass Bay Area, Minnesota, Arizona, Kansas and Central Plains, Mid-Atlantic, and Texas chapters), the Merck, and the National Neurofibromatosis Foundation (NNF) to A.J.S. Y.C. was supported by a Young Investigator Award from NNF.

Li et al.: "The HMG-CoA reductase inhibitor, lovastatin, reverses the learning and attention deficits in a mouse model of Neurofibromatosis Type 1." Publishing in Current Biology, Vol. 15, 1961-1967, November 8, 2005. DOI 10.1016/j.cub.2005.09.043 www.current-biology.com

Cell Press

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