Micromolar concentrations of Zn²⁺ antagonize NMDA and GABA responses of hippocampal neurons

NMDA (N-methyl-D-aspartate) receptors serve as modulators of synaptic transmission in the mammalian central nervous system (CNS) with both short-term and long-lasting effects¹. Divalent cations are pivotal in determining this behaviour in that Mg²⁺ blocks the ion channel in a voltage-dependent manner^2,3, and Ca²⁺ permeates NMDA channels⁴. Zn²⁺ could also modulate neuronal excitability because it is present at high concentrations in brain, especially the synaptic vesicles of mossy fibres in the hippocampus^5,6 and is released with neuronal activity^7,8. Both proconvulsant⁹ and depressant¹⁰ actions of Zn²⁺ have been reported. We have found that zinc is a potent non-competitive antagonist of NMDA responses on cultured hippocampal neurons. Unlike Mg²⁺, the effect of Zn ²⁺ is not voltage-sensitive between -40 and +60 mV, suggesting that Zn²⁺ and Mg²⁺ act at distinct sites. In addition, we have found that Zn²⁺ antagonizes responses to the inhibitory transmitter GABA (γ-aminobutyric acid). Our results provide evidence for an additional metal-binding site on the NMDA receptor channel, and suggest that Zn ²⁺ may regulate both excitatory and inhibitory synaptic transmission in the hippocampus.