Maintained LTP and Memory Are Lost by Zn2+ Influx into Dentate Granule Cells, but Not Ca2+ Influx

The idea that maintained LTP and memory are lost by either increase in intracellular Zn2+ in dentate granule cells or increase in intracellular Ca2+ 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 Zn2+ but not high K+-induced increase in intracellular Ca2+. High K+-induced disturbances of LTP and intracellular Zn2+ 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 Zn2+, but not increase in intracellular Ca2+. NMDA and glucocorticoid, which induced Zn2+ release from the internal stores, did not impair maintained LTP. The present study indicates that increase in Zn2+ influx into dentate granule cells through AMPA receptors loses maintained LTP and memory. Regulation of Zn2+ influx into dentate granule cells is more critical for not only memory acquisition but also memory retention than that of Ca2+ influx.