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The Journal of Neuroscience, July 5, 2006, 26(27):7181-7188; doi:10.1523/JNEUROSCI.1258-06.2006

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Development/Plasticity/Repair
Zinc Modulates Bidirectional Hippocampal Plasticity by Effects on NMDA Receptors

Yukitoshi Izumi,¹ Yves P. Auberson,² and Charles F. Zorumski^1,3

Departments of ¹Psychiatry and ²Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63130, and ³Department of Chemistry, Neuroscience, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland

Correspondence should be addressed to Dr. Charles F. Zorumski, Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Email: zorumskc{at}wustl.edu

Zinc has complex effects on NMDA receptors (NMDARs) and may be an endogenous modulator of synaptic plasticity. In the CA1 region of rat hippocampal slices, we observed that low micromolar concentrations of zinc depress NMDAR synaptic responses by 40–50% and inhibit long-term depression (LTD) but not long-term potentiation (LTP). A combination of zinc plus ifenprodil, an inhibitor of NR1/NR2B receptors, produced no greater inhibition of synaptic NMDARs than either agent alone, suggesting overlapping effects on NMDARs. Similar to low micromolar zinc, ifenprodil inhibited LTD but not LTP. In contrast, low concentrations of 2-amino-5-phosphonovalerate (APV) did not block either LTP or LTD despite producing >50% inhibition of synaptic NMDARs. NVP-AAM077 ([(R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl)-methyl]phosphonic acid), an antagonist with relative NR1/NR2A selectivity at low concentrations, also inhibited synaptic NMDARs by 50% at 0.05 µM but failed to completely block either LTP or LTD. These results suggest that LTD induction depends on specific NMDARs with sensitivity to low micromolar zinc and ifenprodil, but LTP is less dependent on specific NMDAR subtypes. Because high-affinity sites of NR2A are likely occupied by ambient zinc, we also examined effects of extracellular zinc chelators. Zinc chelation blocked LTP but had no effect on LTD. This LTP inhibition was overcome by APV and NVP-AAM077 but not ifenprodil, suggesting that zinc chelation unmasks tonic NR1/NR2A activation that negatively modulates LTP.

Key words: LTP; LTD; ifenprodil; NMDA receptors; synaptic plasticity; metaplasticity

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Received March 23, 2006; revised May 31, 2006; accepted June 1, 2006.

Correspondence should be addressed to Dr. Charles F. Zorumski, Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Email: zorumskc{at}wustl.edu

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