Insight into glutamate excitotoxicity from synaptic zinc homeostasis

Zinc is released from glutamatergic (zincergic) neuron terminals in the hippocampus, followed by the increase in Zn(2+) concentration in the intracellular (cytosol) compartment, as well as that in the extracellular compartment. The increase in Zn(2+) concentration in the intracellular compartment during synaptic excitation is mainly due to Zn(2+) influx through calcium-permeable channels and serves as Zn(2+) signaling as well as the case in the extracellular compartment. Synaptic Zn(2+) homeostasis is important for glutamate signaling and altered under numerous pathological processes such as Alzheimer's disease. Synaptic Zn(2+) homeostasis might be altered in old age, and this alteration might be involved in the pathogenesis and progression of Alzheimer's disease; Zinc may play as a key-mediating factor in the pathophysiology of Alzheimer's disease. This paper summarizes the role of Zn(2+) signaling in glutamate excitotoxicity, which is involved in Alzheimer's disease, to understand the significance of synaptic Zn(2+) homeostasis in the pathophysiology of Alzheimer's disease.