Zinc enhances long-term potentiation through P2X receptor modulation in the hippocampal CA1 region

Zn²⁺ is an essential ion that is stored in and co-released from glutamatergic synapses and it modulates neurotransmitter receptors involved in long-term potentiation (LTP). However, the mechanism(s) underlying Zn²⁺-induced modulation of LTP remain(s) unclear. As the purinergic P2X receptors are relevant targets for Zn²⁺ action, we have studied their role in LTP modulation by Zn²⁺ in the CA1 region of rat hippocampal slices. Induction of LTP in the presence of Zn²⁺ revealed a biphasic effect - 5-50μm enhanced LTP induction, whereas 100-300μm Zn²⁺ inhibited LTP. The involvement of a purinergic mechanism is supported by the fact that application of the P2X receptor antagonists 2',3'-O-(2,4,6-trinitrophenyl) ATP (TNP-ATP) and periodate-oxidized ATP fully abolished the facilitatory effect of Zn²⁺. Notably, application of the P2X₇ receptor-specific antagonist Brilliant Blue G did not modify the Zn²⁺-dependent facilitation of LTP. Exogenous ATP also produced a biphasic effect - 0.1-1μm ATP facilitated LTP, whereas 5-10μm inhibited LTP. The facilitatory effect of ATP was abolished by the application of TNP-ATP and was modified in the presence of 5μm Zn²⁺, suggesting that P2X receptors are involved in LTP induction and that Zn²⁺ leads to an increase in the affinity of P2X receptors for ATP. The latter confirms our previous results from heterologous expression systems. Collectively, our results indicate that Zn²⁺ at low concentrations enhances LTP by modulating P2X receptors. Although it is not yet clear which purinergic receptor subtype(s) is responsible for these effects on LTP, the data presented here suggest that P2X₄ but not P2X₇ is involved.