Brain cholesterol turnover required for geranylgeraniol production and learning in mice.
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.
Kotti
Tiina J
TJ
Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Ramirez
Denise M O
DM
Pfeiffer
Brad E
BE
Huber
Kimberly M
KM
Russell
David W
DW
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D004224:Diterpenes / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013250:Steroid Hydroxylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission
D004224:Diterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; C017338:geranylgeraniol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; D008798:Mevalonic Acid