Brain cholesterol turnover required for geranylgeraniol production and learning in mice

Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3869-74. doi: 10.1073/pnas.0600316103. Epub 2006 Feb 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Cholesterol / metabolism*
  • Cholesterol 24-Hydroxylase
  • Diterpenes / metabolism*
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • In Vitro Techniques
  • Learning / physiology*
  • Long-Term Potentiation / drug effects
  • Mevalonic Acid / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Steroid Hydroxylases / deficiency
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism
  • Synaptic Transmission


  • Diterpenes
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Cholesterol
  • geranylgeraniol
  • Steroid Hydroxylases
  • Cholesterol 24-Hydroxylase
  • Mevalonic Acid