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Prolonged reversal of long-term potentiation that is N-methyl-D-aspartate receptor independent: implications for memory formation.

Reversal of long-term potentiation (LTP) by low-frequency stimulation (LFS) is often referred to as depotentiation (DP), a phenomenon that is time-dependent. The present study aimed to determine whether LTP could still be reversed when the stimulation was applied beyond the optimal time window in hippocampal slices from adult rats. Field excitatory postsynaptic potentials (fEPSPs) were recorded from the strata radiatum in CA1, following stimulation of Schaffer collaterals. Theta-burst stimulation (TBS) induced LTP that could be reversed by repeated paired-pulse LFS (PP-LFS) after almost 3 h post-TBS. Only when synapse strength reached a plateau did application of PP-LFS trigger DP. In addition, it was surprising to observe that PP-LFS, which generally induces LTD in adult rats, evoked an LTP-like further strengthening in previously potentiationed synapses, even in the presence of APV, a competitive antagonist of N-methyl-D-aspartate receptors (NMDA-Rs). Our results suggest that LTP can be reversed NMDAR-independently more than 2 h after TBS by PP-LFS in adult hippocampus and that saturation of LTP is effective to promote this process.