Factors regulating the reversibility of long-term potentiation

Theta burst stimulation (TBS) produces an extremely stable form of long-term potentiation (LTP). In contrast, a brief episode of single-pulse stimulation at theta frequency [theta pulse stimulation (TPS)] has been demonstrated to reverse LTP in area CA1 of slices and freely moving animals without causing depression when administered to nonpotentiated pathways. The present in vitro studies confirm these results and establish that the susceptibility of LTP to reversal and the degree of depotentiation are time-dependent. Specifically, a 1 min train of TPS delivered 30 sec after LTP induction produced an almost complete and lasting depotentiation but had increasingly less impact at longer delays and virtually no effect at 30 min. Increasing the duration of TPS did not cause more depotentiation. However, pharmacological facilitation of AMPA receptor-mediated currents significantly enhanced the strength of the reversal process and allowed TPS to produce robust depotentiation up to 30 min after LTP induction. The reversal effect was selective to potentiated synapses receiving TPS, was reversible, and was not blocked by NMDA receptor antagonism. Additional experiments indicated that AMPA receptor facilitation promotes depotentiation by enhancing an active process triggered by TPS that reverses expression without extending the time course of consolidation. These results suggest that the mechanisms responsible for LTP reversal are linked to the amplitude and/or duration of fast excitatory currents mediated by synaptic AMPA receptors and are effective up to the completion of LTP stabilization.