CHANGES IN PAIRED-PULSE FACILITATION SUGGEST PRESYNAPTIC INVOLVEMENT IN LONG-TERM POTENTIATION

Long-term potentiation (LTP) is a use-dependent form of synaptic plast icity that is of great interest as a potential cellular substrate unde rlying memory. It is important to determine the pre- and/or postsynapt ic locus of LTP expression in order to study its underlying mechanisms . Despite intensive investigation, however, its locus of expression re mains uncertain. It has been hypothesized that it LTP expression inclu des a presynaptic locus then it may alter the expression of another pr esynaptically mediated form of potentiation like paired-pulse facilita tion (PPF), which is an increase in a second population excitatory pos tsynaptic potential when it is elicited shortly after a first. Previou s authors have found no change in PPF in association with LTP. We re-e xamined the hypothesis, however, to reconcile the negative PPF data wi th other data that have suggested presynaptic involvement in LTP. Extr acellular recordings were made in area CA1 of the rat hippocampal slic e preparation. Surprisingly, PPF both increased and decreased signific antly in association with LTP. The changes in PPF occurred in a predic table way, however. They correlated inversely with initial PPF magnitu de so that a larger initial PPF was associated with a decrease in PPF with LTP while a smaller initial PPF was associated with an increase. Because PPF increased or decreased in individual slices in association with LTP, the average PPF of all slices did not change, in agreement with previous studies. The changes in PPF were also specific to LTP; t hat is, they were input specific, were not due to changes in inhibitio n or nonspecific effects of high-frequency stimulation, were not due t o active postsynaptic currents or their nonlinear summation, and PPF c hanged with the same time course as LTP. We conclude that the mechanis m of early LTP expression includes at least the presynaptic locus. Two hypotheses regarding the presynaptic mechanism underlying LTP express ion, which are consistent with finding both increases and decreases in PPF with LTP, are (1) that there is an increase in the number of rele ase sites with LTP or (2) that there is an increase in both the number of release sites and the probability of neurotransmitter release. Inc reases in the probability of neurotransmitter release alone would not appear to account for our findings since such increases have been asso ciated only with decreases in PPF. Out findings do not exclude additio nal postsynaptic involvement. Because of the simplicity of the PPF tec hnique, the few assumptions involved in using it, and the apparent val idity of those assumptions, this would appear to be some of the strong est evidence yet for presynaptic involvement in LTP.