No abstract

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.

Memory is lost by the increased influx of extracellular Zn into neurons. It is possible that intracellular Zn dynamics is modified even at non-zincergic medial perforant pathway-dentate granule cell synapses along with aging and that vulnerability to the modification is linked to age-related cognitive decline. To examine these possibilities, vulnerability of long-term potentiation (LTP) maintenance, which underlies memory retention, to modification of synaptic Zn dynamics was compared between young and aged rats. The influx of extracellular Zn into dentate granule cells was increased in aged rats after injection of high K into the dentate gyrus, but not in young rats. This increase impaired maintained LTP in aged rats. However, the impairment was rescued by co-injection of CaEDTA, an extracellular Zn chelator, or CNQX, an AMPA receptor antagonist, which suppressed the Zn influx. Maintained LTP was also impaired in aged rats after injection of ZnAF-2DA into the dentate gyrus that chelates intracellular Zn, but not in young rats. Interestingly, the capacity of chelating intracellular Zn with intracellular ZnAF-2 was almost lost in the aged dentate gyrus 2 h after injection of ZnAF-2DA into the dentate gyrus, suggesting that intracellular Zn-buffering is weakened in the aged dentate gyrus, compared to the young dentate gyrus. In the dentate gyrus of aged rats, maintained LTP is more vulnerable to modification of intracellular Zn dynamics than in young rats, probably due to weakened intracellular Zn-buffering.