Involvement of N-methyl-D-aspartate receptor subunits in zinc-mediated modification of CA1 long-term potentiation in the developing hippocampus.

Zinc is an endogenous N-methyl-D-aspartate (NMDA) receptor blocker. It is possible that zinc-mediated modification of hippocampal CA1 long-term potentiation (LTP) is linked to the expression of NMDA receptor subunits, which varies with postnatal development. In the present study, the effect of ZnCl(2) and CaEDTA, a membrane-impermeable zinc chelator, on CA1 LTP induction was examined in hippocampal slices from immature (3-week-old) and young (6-week-old) rats. Tetanus (10-100 Hz, 1 sec)-induced CA1 LTP was more greatly enhanced in 3-week-old rats. CA1 LTP was inhibited in the presence of 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, and CaEDTA in 3-week-old rats, as in the case of 6-week-old rats reported previously. In 3-week-old rats, on the other hand, 5 µM ZnCl(2) attenuated NMDA receptor-mediated EPSPs more than in 6-week-old rats and significantly attenuated CA1 LTP. Moreover, 5 µM ZnCl(2) significantly attenuated CA1 LTP in the presence of (2R,4S)-4-(3-phosphonopropyl)-2-piperidinecarboxylic acid (PPPA), an NR2A antagonist, in 3-week-old rats, but not that in the presence of ifenprodil, an NR2B antagonist, suggesting that zinc-mediated attenuation of CA1 LTP is associated with the preferential expression of NR2B subunit in 3-week-old rats. In 6-week-old rats, however, 5 µM ZnCl(2) significantly potentiated CA1 LTP and also CA1 LTP in the presence of PPPA. The present study demonstrates that endogenous zinc may participate in the induction of CA1 LTP. It is likely that the changes in expression of NMDA receptor subunits are involved in the zinc-mediated modification of CA1 LTP in the developing hippocampus.

Zinc differentially acts on components of long-term potentiation at hippocampal CA1 synapses.

Long-term potentiation (LTP) at hippocampal CA1 synapses consists of N-methyl-d-aspartate (NMDA) receptor-dependent and NMDA receptor-independent forms. The action of divalent heavy metals, which are NMDA receptor antagonists, was examined focusing on the evidence that CA1 LTP induced by a 100-Hz tetanus for 1s is abolished in the presence of 2-amino-5-phosphonovalerate (APV), a NMDA receptor antagonist. Only ZnCl2 (5microM) of heavy metals tested potentiated CA1 LTP. CA1 LTP induced by repeated 100-Hz tetanus (1s, 6 times, 10min interval), which reached a plateau in magnitude, was abolished in the presence of 50microM APV. In this case, CA1 LTP after the first tetanus was potentiated in the presence of 5microM ZnCl2, whereas CA1 LTP after the last tetanus was not potentiated. These results indicate that the magnitude of NMDA receptor-dependent CA1 LTP can be positively shifted with 5microM ZnCl2 in the range of the maximum magnitude. CA1 LTP induced by a 200-Hz tetanus for 1s was not potentiated in the presence of 5microM ZnCl2 and was partially inhibited in the presence of APV. Furthermore, CA1 LTP induced by a 200-Hz tetanus for 1s in the presence of APV was not potentiated in the presence of 5microM ZnCl2, indicating that NMDA receptor-independent CA1 LTP is not potentiated with 5microM ZnCl2. The present study suggests that zinc differentially acts on CA1 LTP components.