Although long-term potentiation (LTP) is long-lasting, it is not permanent and decays within weeks after its induction. Little is known about the processes underlying this decay. Here we assessed the contribution of synaptic activity to LTP decay by determining the effect of the competitive NMDA receptor antagonist CPP on the decay of perforant path-dentate LTP. CPP blocked decay over a one-week period when administered daily following the induction of LTP, and blocked decay of the late, protein-synthesis-dependent phase of LTP when administered two days after LTP induction. CPP administered for a five-day period following spatial memory training enhanced subsequent memory retention. These data suggest that LTP is normally a persistent process that is actively reversed by NMDA receptor activation, and that both the early and late phases of LTP are dynamic processes regulated by NMDA receptors. These data also support the view that LTP is involved in maintaining spatial memory.

The induction of long-term potentiation (LTP) in the hippocampal formation can be modulated by different behavioral states. However, few studies have addressed modulation of LTP during behavioral states in which the animal is likely acquiring new information. Here, we demonstrate that both the induction and the longevity of LTP in the dentate gyrus are enhanced when LTP is induced during the initial exploration of a novel environment. These effects are independent from locomotor activity, changes in brain temperature, and theta rhythm. Previous exposure to the novel environment attenuated this enhancement, suggesting that the effects of novelty habituate with familiarity. LTP longevity also was enhanced when induced in familiar environments containing novel objects. Together, these data indicate that both LTP induction and maintenance are enhanced when LTP is induced while rats investigate novel stimuli. We suggest that novelty initiates a transition of the hippocampal formation to a mode that is particularly conducive to synaptic plasticity, a process that could allow for new learning while preserving the stability of previously stored information. In addition, LTP induced in novel environments elicited a sustained late LTP. This suggests that a single synaptic population can display distinct profiles of LTP maintenance and that this depends on the animal's behavioral state during its induction. Furthermore, the duration of LTP enhanced by novelty parallels the time period during which the hippocampal formation is thought necessary for memory, consistent with the view that dentate LTP is of a duration sufficient to sustain memory in the hippocampal formation.

Long-term potentiation (LTP), a relatively long-lived increase in synaptic strength, remains the mot popular model for the cellular process that may underlie information storage within neural systems. The strongest arguments for a role of LTP in memory are theoretical and involve Hebb's Postulate, Marr's theory of hippocampal function, and neural network theory. Considering LTP research as a whole, few studies have addressed the essential question: Is LTP a process involved in learning and memory? The present manuscript reviews research that attempts to link LTP with learning and memory, focusing on studies utilizing electrophysiological, pharmacological, and molecular biological methodologies. Most evidence firmly supports a role for LTP in learning memory. However, an unequivocal experimental demonstration of a contribution of LTP to memory is hampered by our lack of knowledge of the biological basis of memory and of the ways in which memories are represented in ensembles of neurons, the existence of a variety of cellular forms of LTP, and the likely resistance of distributed memory stores to degradation by treatments that incompletely disrupt LTP.

Derrick. Long-term potentiation in direct perforant path projections to the hippocampal CA3 region in vivo. J Neurophysiol 87: 669 -678, 2002; 10.1152/jn.00938.2000. The perforant path constitutes the primary projection system relaying information from the neocortex to the hippocampal formation. Long-term synaptic potentiation (LTP) in the perforant path projections to the dentate gyrus is well characterized. However, surprisingly few studies have addressed the mechanisms underlying LTP induction in the direct perforant path projections to the hippocampus. Here we investigate the role of N-methyl-D-aspartate (NMDA) and opioid receptors in the induction of LTP in monosynaptic medial and lateral perforant path projections to the CA3 region in adult pentobarbital sodium-anesthetized rats. Similar to LTP observed at the medial perforant path-dentate gyrus synapse, medial perforant path-CA3 synapses display LTP that is blocked by both local and systemic administration of the competitive NMDA receptor antagonist (Ϯ)-3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid [(Ϯ)-CPP]. By contrast, LTP induced at the lateral perforant path-CA3 synapses is not blocked by either local or systemic administration of this NMDA receptor antagonist. The induction of LTP at lateral perforant path-CA3 synapses, which is blocked by the opioid receptor antagonist naloxone, is also blocked by the selective mu () opioid receptor antagonist Cys 2 -Tyr 3 -Orn 5 -Pen 7 -amide (CTOP), but not the selective delta (␦) opioid receptor antagonist naltrindole (NTI). CTOP was without effect on the induction of medial perforant path-CA3 LTP. The selective sensitivity of lateral perforant path-CA3 LTP to -opioid receptor antagonists corresponds with the distribution of -opioid receptors within the stratum lacunosum-moleculare of area CA3 where perforant path projections to CA3 terminate. These data indicate that both lateral and medial perforant path projections to the CA3 region display LTP, and that LTP induction in medial and lateral perforant path-CA3 synapses are differentially sensitive to NMDA receptor and -opioid receptor antagonists. This suggests a role for opioid, but not NMDA receptors in the induction of LTP at lateral perforant path projections to the hippocampal formation.

Because exogenous application of a number of cytokines and growth factors can alter synaptic properties, we sought to determine if endogenous cytokine expression is affected by neuronal activity. In addition, we examined whether cytokine expression is altered by the techniques used to stimulate and record from hippocampal neurons. Using semi-quantitative RNase protection and RT-PCR assays, we studied the expression of 18 cytokine, growth factor, and receptor genes in the hippocampus following the induction of Schaffer collateral-CA1 long-term potentiation (LTP). We found that various cytokines are dramatically induced following preparation of slices for in vitro recording and as a result of injury following acute electrode placement in vivo. These increases can be overcome in vivo, however, using permanent electrodes implanted three weeks prior to testing. Using this chronic preparation, we found that interleukin-6 (IL-6) mRNA was upregulated nearly 20-fold by LTP induction in vivo, marking the first demonstration of endogenous regulation of this cytokine in response to LTP. In situ hybridization for IL-6 revealed that upregulation is tightly localized near the site of stimulation and is detected only in non-neuronal cells, identified as GFAP+ astrocytes and GFAP− cells within proximal blood vessels. Coupled with previous results showing that exogenously applied IL-6 can prevent the induction of LTP, this finding suggests a mechanism by which the local release of a cytokine could regulate LTP at nearby sites.

No abstract

No abstract

The contribution of high-frequency synaptic activity to the induction of long-term potentiation (LTP) in the opioid peptide-containing mossy fiber projection was investigated in vivo in anesthetized rats. Because high-frequency mossy fiber activity is essential for both the release of opioid peptides and the induction of mossy fiber LTP, we investigated whether the activation of opioid receptors underlies the requirement of sustained high-frequency mossy fiber activity for LTP induction. Mossy fiber responses were found to have a distinct threshold for the number of 100 Hz pulses necessary to induce LTP, with bursts of 25-30 pulses being the minimum for LTP induction. Application of 1 nmol of the mu-opioid receptor agonist DAMGO to the CA3 region potentiated mossy fiber responses, but, unlike for mossy fiber LTP, this potentiation could be reversed by mu-opioid receptor antagonist CTOP. Stimulation of the mossy fibers with either a single burst of 15 pulses at 100 Hz or application of 100 pmol of DAMGO was ineffective in potentiating mossy fiber responses. However, delivery of a 15 pulse burst 10 min following DAMGO application was effective in potentiating mossy fiber responses. This potentiation was not reversed by CTOP and it occluded stimulation-induced LTP, suggesting that brief bursts delivered in the presence of DAMGO had induced mossy fiber LTP. The release of opioid peptides and the resulting activation of mu-opioid receptors is suggested as one factor that underlies the requirement of sustained high-frequency stimulation for the induction of mossy fiber LTP.(ABSTRACT TRUNCATED AT 250 WORDS)