| First Author | Kotti TJ | Year | 2006 |
| Journal | Proc Natl Acad Sci U S A | Volume | 103 |
| Issue | 10 | Pages | 3869-74 |
| PubMed ID | 16505352 | Mgi Jnum | J:107142 |
| Mgi Id | MGI:3620343 | Doi | 10.1073/pnas.0600316103 |
| Citation | Kotti TJ, et al. (2006) Brain cholesterol turnover required for geranylgeraniol production and learning in mice. Proc Natl Acad Sci U S A 103(10):3869-74 |
| abstractText | 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. |
