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

Abstract

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.

Keywords: Hippocampus; Memory; Mossy fiber; Perforant pathway; Schaffer collateral; Zinc.