Significance of synaptic Zn2+ signaling in zincergic and non-zincergic synapses in the hippocampus in cognition

A portion of zinc concentrates in the synaptic vesicles in the brain and is released from glutamatergic (zincergic) neuron terminals. It serves as a signaling factor (in a form of free Zn2+). Both extracellular Zn2+ signaling, which predominantly originates in Zn2+ release from zincergic neuron terminals, and intracellular Zn2+ signaling, which is often linked to extracellular Zn2+ signaling, are involved in hippocampus-dependent memory. At mossy fiber-CA3 pyramidal cell synapses and Schaffer collateral-CA1 pyramidal cell synapses, which are zincergic, extracellular Zn2+ signaling leads to intracellular Zn2+ signaling and is involved in learning and memory. At medial perforant pathway-dentate granule cell synapses, which are non-zincergic, intracellular Zn2+ signaling, which originates in the internal stores containing Zn2+, is involved in learning and memory. The blockade of Zn2+ signaling with Zn2+ chelators induces memory deficit, while the optimal amount range of Zn2+ signaling is unknown. It is possible that the degree and frequency of Zn2+ signaling, which determine the increased Zn2+ levels, modulates learning and memory as well as intracellular Ca2+ signaling. To understand the precise role of synaptic Zn2+ signaling in the hippocampus, the present paper summarizes the current knowledge on Zn2+ signaling at zincergic and non-zincergic synapses in the hippocampus in cognition and involvement of zinc transporters and zinc-binding proteins in synaptic Zn2+ signaling.