Influx of extracellular Zn2+ into the hippocampal CA1 neurons is required for cognitive performance via long-term potentiation

•Block of Zn2+ influx in the hippocampal CA1 inhibits in vivo CA1 LTP.•Block of Zn2+ influx in the hippocampal CA1 impairs object recognition.•Excess Zn2+ influx in the hippocampal CA1 inhibits in vivo CA1 LTP.•The extent of Zn2+ influx in the CA1 is critical for CA1 LTP and cognition.

Physiological significance of synaptic Zn2+ signaling was examined in the CA1 of young rats. In vivo CA1 long-term potentiation (LTP) was induced using a recording electrode attached to a microdialysis probe and the recording region was locally perfused with artificial cerebrospinal fluid (ACSF) via the microdialysis probe. In vivo CA1 LTP was inhibited under perfusion with CaEDTA and ZnAF-2DA, extracellular and intracellular Zn2+ chelators, respectively, suggesting that the influx of extracellular Zn2+ is required for in vivo CA1 LTP induction. The increase in intracellular Zn2+ was chelated with intracellular ZnAF-2 in the CA1 1 h after local injection of ZnAF-2DA into the CA1, suggesting that intracellular Zn2+ signaling induced during learning is blocked with intracellular ZnAF-2 when the learning was performed 1 h after ZnAF-2DA injection. Object recognition was affected when training of object recognition test was performed 1 h after ZnAF-2DA injection. These data suggest that intracellular Zn2+ signaling in the CA1 is required for object recognition memory via LTP. Surprisingly, in vivo CA1 LTP was affected under perfusion with 0.1-1 μM ZnCl2, unlike the previous data that in vitro CA1 LTP was enhanced in the presence of 1-5 μM ZnCl2. The influx of extracellular Zn2+ into CA1 pyramidal cells has bidirectional action in CA1 LTP. The present study indicates that the degree of extracellular Zn2+ influx into CA1 neurons is critical for LTP and cognitive performance.

Graphical abstractDownload high-res image (203KB)Download full-size image