The relationship between tetanus intensity and the magnitude of hippocampal long-term potentiation in vivo

In this study, we assessed the effects of varying tetanus and test-pulse intensity on the magnitude of long-term potentiation (LTP) in the perforant path–dentate gyrus projection of urethane-anaesthetized rats. We developed a novel within-subjects procedure in which test-pulse-stimulation intensity (60–1000 μA) was varied quasi-randomly under computer control throughout the recording period. After a baseline period, we applied a high-frequency tetanus, the intensity of which was varied over the same range as test-pulse intensity, but between subjects. The time-course of LTP was thus monitored continuously across a range of test-pulse intensities in each rat. Intense high-frequency tetanization at 1000 μA resulted in a paradoxical depression of the dentate field excitatory post-synaptic potential (fEPSP) slope at the lowest test intensity used (60 μA), but caused a potentiation at higher test intensities in the same animal. Moreover, intense tetanization induced less LTP than a moderate tetanus over most of the test-intensity range. Explanations for this pattern of data include a potentiation of feed-forward inhibition in conjunction with LTP of excitatory neurotransmission, or local tissue damage at the stimulation site. To address this issue, we conducted an additional experiment in which a second stimulating electrode was placed in the perforant path at a site closer to the dentate, in order to activate a common population of afferents at a location ‘downstream’ of the original stimulation site. After 1000-μA tetanization of the original (‘upstream’) site, fEPSPs were again depressed in response to test stimulation of the upstream site, but only potentiation was observed in response to stimulation of the downstream site. This is consistent with the idea that the depression induced by intense tetanization results from local changes at the stimulation site. In conclusion, while tetanus intensity must exceed the LTP induction threshold, intensities above 500 μA should be avoided; in the present study, tetanization at 250–500 μA yielded maximal levels of LTP