Abstract
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 (60–1000μA) 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 1000μA resulted in a paradoxical depression of the dentate field excitatory post-synaptic potential (fEPSP) slope at the lowest test intensity used (60μA), 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 500μA should be avoided; in the present study, tetanization at 250–500μA yielded maximal levels of LTP.
Highlights
The induction of long-term potentiation (LTP) by the delivery of high-frequency tetanic stimulation is commonly used to assess the capacity for synaptic change in rodents following drug administration or genetic alteration (Martin et al, 2000)
The results of experiment 1 confirm that, within the same animal, a strong tetanus produces a depression of the dentate field excitatory post-synaptic potential (fEPSP) elicited by weak test stimulation, whereas a potentiation of the response is observed at higher test intensities
Typical examples of fEPSPs elicited by 1000-lA test stimulation at both sites are shown. (B) The time course of LTP at each test intensity elicited by a 1000-lA upstream tetanus
Summary
The induction of long-term potentiation (LTP) by the delivery of high-frequency tetanic stimulation is commonly used to assess the capacity for synaptic change in rodents following drug administration or genetic alteration (Martin et al, 2000). The stimulation current used to sample fEPSPs before and after tetanization provides one example: low-intensity test pulses typically result in a larger percentage increase in fEPSP slope than high-intensity test stimulation, a phenomenon attributed to the increasingly non-linear summation of individual post-synaptic potentials as large numbers of afferent fibres are recruited (Jeffery, 1995). Strong tetanization sometimes results in a paradoxical depression of the fEPSP slope at low test-pulse intensities (Hodgson et al, 1997; Trepel and Racine, 1998). This is a potential concern if, as is sometimes the case, the chosen tetanus protocol involves increasing the tetanization current substantially above the intensity used for test-pulse stimulation
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