Significance of Zn2+ signaling in cognition: Insight from synaptic Zn2+ dyshomeostasis

Zinc is concentrated in the synaptic vesicles via zinc transporter-3 (ZnT3), released from glutamatergic (zincergic) neuron terminals, and serves as a signal factor (Zn2+ signal) in the intracellular (cytosol) compartment as well as in the extracellular compartment. Synaptic Zn2+ signaling is dynamically linked to neurotransmission via glutamate and is involved in synaptic plasticity such as long-term potentiation (LTP) and cognitive activity. Zinc concentration in the synaptic vesicles is correlated with ZnT3 protein expression and potentially decreased under chronic zinc deficiency. Synaptic vesicle serves as a large pool for Zn2+ signaling and other organelles might also serve as a pool for Zn2+ signaling. ZnT3KO mice and zinc-deficient animals, which lack or reduce Zn2+ release into the extracellular space by action potentials, are able to recognize novel or displaced objects normally. However, the amount of Zn2+ functioning as a signal factor increases along with brain development. Exogenous Zn2+ lowers the threshold in hippocampal CA1 LTP induction in young rat. Furthermore, ZnT3KO mice lose advanced cognition such as contextual discrimination. It is likely that the optimal range of synaptic Zn2+ signaling is involved in cognitive activity. On the basis of the findings on the relationship between dyshomeostasis of synaptic Zn2+ and cognition, this paper summarizes the possible involvement of intracellular Zn2+ signaling in cognitive ability.