Insight into cognitive decline from Zn2+ dynamics through extracellular signaling of glutamate and glucocorticoids

Glutamatergic neuron activity and/or the modification of the activity with glucocorticoids are closely linked to synaptic Zn2+ dynamics as well as synaptic Ca2+ dynamics. The dynamic crosstalk of synaptic Zn2+ signaling to intracellular Ca2+ signaling via calcium channels is involved in synaptic plasticity such as long-term potentiation (LTP) and cognitive activity. The influx of extracellular Zn2+ into postsynaptic neurons, which is closely linked to glutamate signaling in the synaptic cleft, is critical for cognitive activity. However, excess intracellular Zn2+ signaling induced by excess glutamatergic neuron activity is involved in not only cognitive decline in neurological disorders but also stress-induced cognitive decline. On the other hand, it has been recognized that excess Ca2+ influx into postsynaptic neurons induces neuronal death, while the involvement of excess intracellular Ca2+ signaling in cognitive decline is poorly understood. Understanding of synaptic Zn2+ dynamics, which are modified by glutamate and glucocorticoid signaling, may be meaningful to prevent Zn2+-mediated cognitive decline. This paper summarizes the current knowledge on Zn2+ dynamics under changing synaptic environment and its impact on cognitive decline.