Zinc is essential for the growth and function of the brain and dietary zinc deficiency causes abnormal behavior. A part of zinc in the brain functions as zinc ion (Zn
2+). Zn
2+ concentrations in the intracellular and extracellular fluid in the hippocampus are estimated to be ~100 pM and ~10 nM, respectively. Extracellular Zn
2+ dynamics in the hippocampus is involved in both cognitive activity and its decline, and dynamically influenced by extracellular glutamate concentration and amyloid β
1-42, a causative peptide of Alzheimer’s disease. Extracellular Zn
2+ concentration in the hippocampus is increased along with aging. The age-related increase in extracellular Zn
2+ leads to intracellular Zn
2+ dysregulation in the neuron, followed by cognitive decline and neurodegeneration. Therefore, intracellular Zn
2+ dysregulation is a risk factor of age-related neurodegenerative disorders. On the other hand, metallothionein, an intracellular Zn
2+-binding protein, plays a key role for intracellular Zn
2+ homeostasis and is also closely linked to hippocampal function. On the basis of our studies, here we review Zn
2+ function and its toxicity in the hippocampus.
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