New insight into metallomics in cognition

Abstract

Brain zinc homeostasis is strictly controlled under healthy condition, indicating the importance of zinc for physiological functions in the brain. A portion of zinc exists in the synaptic vesicles and is released from glutamatergic (zincergic) neuron terminals. The zinc serves as a signal factor (as Zn2+) in the intracellular (cytosol) compartment, in addition to the extracellular compartment. 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. Intracellular Zn2+ signaling is critical for cognitive activity as well as intracellular Ca2+ signaling. On the other hand, excess intracellular Zn2+ signaling, which is induced by excess glutamatergic neuron activity, is involved in neuronal death in neurological disorders as well as excess intracellular Ca2+ signaling. The hypothalamic-pituitary-adrenal (HPA) axis activity, i.e., glucocorticoid secretion, can potentiate glutamatergic neuron activity and modify synaptic Zn2+ signaling. This activity is enhanced by stress, aging, and zinc-deficient diet. Synaptic Zn2+ signaling is critical in both functional and pathological aspects and involved in β-amyloid-mediated cognitive decline. This chapter summarizes the physiological significance of intracellular Zn2+ signaling in cognition, in association with other divalent metals.