Rapid Intracellular Zn Dysregulation via Membrane Corticosteroid Receptor Activation Affects In Vivo CA1 LTP.

Involvement of membrane mineralocorticoid (MC) and glucocorticoid (GC) receptors in synaptic Zn dynamics remains unclear. Here, we tested whether synaptic plasticity is affected by rapid intracellular Zn dysregulation via membrane MC and GC receptor activation, in comparison with intracellular Ca dysregulation. In anesthetized rats, extracellular Zn level was increased under local perfusion of the hippocampal CA1 with 500 ng/ml corticosterone. In vivo CA1 long-term potentiation (LTP) at Schaffer collateral-CA1 pyramidal cell synapses was attenuated by the pre-perfusion with corticosterone prior to tetanic stimulation, and the attenuation was canceled by co-perfusion with CaEDTA, an extracellular Zn chelator, suggesting that corticosterone-induced increase in extracellular Zn is involved in the subsequent attenuation of LTP. In rat brain slices, corticosterone-induced increases in extracellular and intracellular Zn were blocked in the presence of spironolactone, a MC receptor antagonist that canceled corticosterone-induced attenuation of LTP. Mifepristone, a GC receptor antagonist, which canceled corticosterone-induced attenuation of LTP, also blocked corticosterone-induced increase in intracellular Zn, but not extracellular Zn. Moreover, corticosterone-induced decrease in phosphorylated CaMKII was restored in the presence of CaEDTA or spironolactone. These results indicate that glucocorticoid rapidly induces the increase in intracellular Zn, which occurs via membrane MC and GC receptor activations, and decreases phosphorylated CaMKII level, resulting in attenuating LTP. Membrane MC and GC receptors induce intracellular Zn dysregulation via differential mechanisms. In contrast, glucocorticoid-induced intracellular Ca dysregulation is not crucial for affecting LTP.