Maintained LTP and Memory Are Lost by Zn Influx into Dentate Granule Cells, but Not Ca Influx

The idea that maintained LTP and memory are lost by either increase in intracellular Zn in dentate granule cells or increase in intracellular Ca was examined to clarify significance of the increases induced by excess synapse excitation. Both maintained LTP and space memory were impaired by injection of high K into the dentate gyrus, but rescued by co-injection of CaEDTA, which blocked high K-induced increase in intracellular Zn but not high K-induced increase in intracellular Ca. High K-induced disturbances of LTP and intracellular Zn are rescued by co-injection of 6-cyano-7-nitroquinoxakine-2,3-dione, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist, but not by co-injection of blockers of NMDA receptors, metabotropic glutamate receptors, and voltage-dependent calcium channels. Furthermore, AMPA impaired maintained LTP and the impairment was also rescued by co-injection of CaEDTA, which blocked increase in intracellular Zn, but not increase in intracellular Ca. NMDA and glucocorticoid, which induced Zn release from the internal stores, did not impair maintained LTP. The present study indicates that increase in Zn influx into dentate granule cells through AMPA receptors loses maintained LTP and memory. Regulation of Zn influx into dentate granule cells is more critical for not only memory acquisition but also memory retention than that of Ca influx.