Brain cholesterol turnover required for geranylgeraniol production and learning in mice

Proceedings of the National Academy of Sciences of the United States of America - Tập 103 Số 10 - Trang 3869-3874 - 2006
Tiina Kotti1, Denise M.O. Ramirez2,3, Brad E. Pfeiffer4,5, Kimberly M. Huber4,5, David W. Russell2
1Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
2Departments of Molecular Genetics and
3Neurology & Neurotherapeutics
4Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390
5Physiology and

Tóm tắt

The mevalonate pathway produces cholesterol and nonsterol isoprenoids, such as geranylgeraniol. In the brain, a fraction of cholesterol is metabolized in neurons by the enzyme cholesterol 24-hydroxylase, and this depletion activates the mevalonate pathway. Brains from mice lacking 24-hydroxylase excrete cholesterol more slowly, and the tissue compensates by suppressing the mevalonate pathway. Here we report that this suppression causes a defect in learning. 24-Hydroxylase knockout mice exhibit severe deficiencies in spatial, associative, and motor learning, and in hippocampal long-term potentiation (LTP). Acute treatment of wild-type hippocampal slices with an inhibitor of the mevalonate pathway (a statin) also impairs LTP. The effects of statin treatment and genetic elimination of 24-hydroxylase on LTP are reversed by a 20-min treatment with geranylgeraniol but not by cholesterol. We conclude that cholesterol turnover in brain activates the mevalonate pathway and that a constant production of geranylgeraniol in a small subset of neurons is required for LTP and learning.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 103 Số 10

3869-3874

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