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Mice deficient in cholesterol 24-hydroxylase exhibit reduced rates of cholesterol synthesis and other non-sterol isoprenoids that arise from the mevalonate pathway. These metabolic abnormalities, in turn, impair learning in the whole animal and hippocampal long-term potentiation (LTP) in vitro. Here, we report pharmacogenetic experiments in hippocampal slices from wild-type and mutant mice that characterize the dependence of LTP on the non-sterol isoprenoid, geranylgeraniol. Addition of geranylgeraniol to slices from 24-hydroxylase knockout mice restores LTP to wild-type levels; however, farnesol, a chemically related compound, does not substitute for geranylgeraniol nor does another animal model of impaired LTP (apolipoprotein E deficiency) respond to this isoprenoid. The requirement for geranylgeraniol is independent of acute protein isoprenylation as judged in experiments employing cell-permeable inhibitors of protein farnesyl transferase and geranylgeranyl transferase enzymes and in mutant mice hypomorphic for geranylgeranyltransferase II. Time course studies show that geranylgeraniol acts within 5 min and at 2 different times during the establishment of LTP: just before electrical stimulation and approximately 15 min thereafter. Localized delivery of geranylgeraniol to the dendritic trees of CA1 hippocampal neurons via the recording electrode is sufficient to restore LTP in slices from 24-hydroxylase knockout mice. We conclude that geranylgeraniol acts specifically and quickly to affect LTP in the Schaffer collaterals of the hippocampus.

Biphasic requirement for geranylgeraniol in hippocampal long-term potentiation