The Impact of Synaptic Zn²⁺ Dynamics on Cognition and Its Decline

The basal levels of extracellular Zn²⁺ are in the range of low nanomolar concentrations and less attention has been paid to Zn²⁺, compared to Ca²⁺, for synaptic activity. However, extracellular Zn²⁺ is necessary for synaptic activity. The basal levels of extracellular zinc are age-dependently increased in the rat hippocampus, implying that the basal levels of extracellular Zn²⁺ are also increased age-dependently and that extracellular Zn²⁺ dynamics are linked with age-related cognitive function and dysfunction. In the hippocampus, the influx of extracellular Zn²⁺ into postsynaptic neurons, which is often linked with Zn²⁺ release from neuron terminals, is critical for cognitive activity via long-term potentiation (LTP). In contrast, the excess influx of extracellular Zn²⁺ into postsynaptic neurons induces cognitive decline. Interestingly, the excess influx of extracellular Zn²⁺ more readily occurs in aged dentate granule cells and intracellular Zn²⁺-buffering, which is assessed with ZnAF-2DA, is weakened in the aged dentate granule cells. Characteristics (easiness) of extracellular Zn²⁺ influx seem to be linked with the weakened intracellular Zn²⁺-buffering in the aged dentate gyrus. This paper deals with the impact of synaptic Zn²⁺ signaling on cognition and its decline in comparison with synaptic Ca²⁺ signaling.