Excess influx of Zn2+ into dentate granule cells affects object recognition memory via attenuated LTP

Abstract

The influx of extracellular Zn2+ into dentate granule cells is nonessential for dentate gyrus long-term potentiation (LTP) and the physiological significance of extracellular Zn2+ dynamics is unknown in the dentate gyrus. Excess increase in extracellular Zn2+ in the hippocampal CA1, which is induced with excitation of zincergic neurons, induces memory deficit via excess influx of Zn2+ into CA1 pyramidal cells. In the present study, it was examined whether extracellular Zn2+ induces object recognition memory deficit via excess influx of Zn2+ into dentate granule cells. KCl (100 mM, 2 µl) was locally injected into the dentate gyrus. The increase in intracellular Zn2+ in dentate granule cells induced with high K+ was blocked by co-injection of CaEDTA and CNQX, an extracellular Zn2+ chelator and an AMPA receptor antagonist, respectively, suggesting that high K+ increases the influx of Zn2+ into dentate granule cells via AMPA receptor activation. Dentate gyrus LTP induction was attenuated 1 h after KCl injection into the dentate gyrus and also attenuated when KCl was injected 5 min after the induction. Memory deficit was induced when training of object recognition test was performed 1 h after KCl injection into the dentate gyrus and also induced when KCl was injected 5 min after the training. High K+-induced impairments of LTP and memory were rescued by co-injection of CaEDTA. These results indicate that excess influx of Zn2+ into dentate granule cells via AMPA receptor activation affects object recognition memory via attenuated LTP induction. Even in the dentate gyrus where is scarcely innervated by zincergic neurons, it is likely that extracellular Zn2+ homeostasis is strictly regulated for cognition.