Inhibition by compactin demonstrates a requirement of isoprenoid metabolism for long-term potentiation in rat hippocampal slices.
Hippocampal long-term potentiation of synaptic transmission is the primary experimental model of learning and memory in the vertebrate brain. However, the detailed intracellular mechanisms giving rise to this persistent increase in synaptic efficacy remain incompletely understood. Mevalonic acid constitutes the basic precursor not only for cholesterol, dolichol and ubichinone but also for farnesyl-pyrophosphate and geranylgeranylpyrophosphate, which are required for post-translational modification of proteins. We have used the specific 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, compactin, to examine the role of isoprenoid metabolism for long-term potentiation in rat hippocampal slices. Compactin was applied at a concentration of 25 microM for 70 min before and during tetanization and the orthodromic population spike amplitude and field excitatory postsynaptic potentials were recorded from CA1 pyramidal cells. Compactin had no effect on the initial tetanization. However, compactin-treated slices were not able to maintain long-term potentiation for more than 60 min and population spike as well as field excitatory postsynaptic potentiation returned to basal levels after 120 min. When the slices were retetanized after 180 min, an almost full potentiation of the population spike and an only partial potentiation of the field excitatory postsynaptic potentials were observed. These results suggest an essential role of isoprenoid intermediates for maintenance of hippocampal long-term potentiation.
Matthies
H
H
Institute of Pharmacology and Toxicology, Faculty of Medicine, Otto-von-Guericke University, Magdeburg, Germany.
Schulz
S
S
Hollt
V
V
Krug
M
M
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D017368:Protein Prenylation; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; C012258:mevastatin; D008148:Lovastatin