The conditions responsible for the associative properties of long-term potentiation (LTP) were examined in the CA1 region of the hippocampal slice preparation. Intracellularly recorded EPSPs resulting from single-volley stimulation at low frequency (0.15-0.1 Hz) in the stratum radiatum or oriens were paired with depolarizing current pulses (50-100 msec) injected through the recording microelectrode. It is shown that these EPSPs, when paired with pulses of sufficient magnitude, become potentiated. This potentiation generally reached a peak after 20-30 pairing events and could outlast the conditioning period by more than 1 hr. It was specific to the paired input, was blocked by 2-amino-5-phosphonovalerate (APV) and was largely blocked by prior homosynaptic tetanization (and vice versa). In experiments performed with picrotoxin (PTX) in the bath, EPSPs were potentiated using 2-4 nA current pulses, with somewhat higher values in normal solution. The effective current pulses, in both normal and PTX solution, produced a repetitive spike discharge of 7-11 spikes (per 100 msec), and within this range, higher frequencies were associated with larger potentiations. However, since similar degrees of EPSP potentiation were observed following blockade of spike activity by intracellular QX-314, spike activity was not the primary conditioning factor. For the potentiation to appear, the EPSP had to occur together with the current pulse or precede it by less than about 100 msec. No potentiation was observed when the EPSP immediately succeeded the pulse. The results suggest that the cooperativity aspect of LTP is related to a need for sufficient postsynaptic depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

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N-methyl-D-aspartate (NMDA) receptor/channel antagonists have previously been shown to impair spatial working memory and hippocampal long-term potentiation. The present experiment investigated the effects of a variety of doses of NMDA antagonists on a working memory task in rats involving an auditory delayed conditional discrimination. Signal detection analysis and an exponential memory decay model were used to extract independent measures of stimulus discriminability and rate of forgetting. A competitive NMDA antagonist, (CPP, 0.33, 1.0, 10.0 mg/kg, IP) produced a reduction in discriminability which was linearly related to log dose, but which was only clear at the 10 mg/kg dose. Rate of forgetting was not increased by any dose. Similar results were obtained with a non-competitive antagonist (MK-801, 0.1, 0.33 mg/kg, IP). These data suggest that doses of NMDA receptor channel antagonists sufficient to disrupt hippocampal long-term potentiation and radial arm maze performance will also disrupt delayed conditional discrimination. The effect on delayed conditional discrimination is due to a disruption of stimulus discriminability and not to an increased rate of forgetting. The extent to which these effects relate to the reported changes in hippocampal long-term potentiation and radial arm maze performance remains to be determined.

Long-term changes in gene expression appear to be critical to the formation of memory, but little is known about its stimulus- transcription coupling. Numerous studies in the last decade, by focusing on unraveling this signal transduction pathway, have investigated the potential role of the immediate-early genes in this process. The krox family of immediate-early gene proteins are of particular interest because they may be involved in stabilizing the synaptic modifications that underlie hippocampal long-term potentiation (LTP). A potential upstream mediator of krox induction is cyclic AMP-responsive element binding protein (CREB), a posttranslationally activated transcription factor that has been implicated in numerous memory paradigms. In this study we investigated whether the activation of CREB by phosphorylation may have a role in the development of rat perforant- path-stimulated LTP and associated dentate granule cell krox-24 mRNA expression. Contrary to what was expected, we failed to show any difference in the levels of phosphorylated CREB after LTP or following endogenous synaptic facilitation stimulated by novelty. Using these same model systems we also investigated the protein levels of brain- derived neurotrophic factor (BDNF), another immediate-early gene that is induced following a durable form of LTP. However, BDNF protein was not induced within the hippocampus after LTP and was transiently decreased following novel environmental stimulation.

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