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NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay


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.

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Figure 1: Efficacy of a 10-mg/kg dose of the NMDA receptor antagonist CPP on LTP induced 12 and 24 h following administration.
Figure 2: Administration of CPP blocks LTP decay.
Figure 3: CPP blocks the decay of late-phase LTP.
Figure 4: CPP enhances retention of spatial memory.


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The authors thank C. Wilson and B.J. Claiborne for comments on the manuscript, J. Bustamante, J. Burrell and B. Agrawal for technical support, and A. Gulledge for suggesting tests of spatial memory. Supported by NIDA (DA01983).

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Correspondence to Brian E. Derrick.

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Villarreal, D., Do, V., Haddad, E. et al. NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay. Nat Neurosci 5, 48–52 (2002).

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