Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 10, Pages 3869-3874Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0600316103
Keywords
cholesterol 24-hydroxylase; isoprenoids; neurons; synaptic plasticity; cytochrome P450
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Funding
- NHLBI NIH HHS [HL20948, P01 HL020948] Funding Source: Medline
- NINDS NIH HHS [NS045711, R01 NS045711] Funding Source: Medline
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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 LTIP 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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