Intracellular Zn2+ signaling in cognition

Brain zinc homeostasis is strictly controlled under healthy conditions, indicating the importance of zinc for physiological function in the brain. A part of zinc in the brain exists in the synaptic vesicles, is released from a subclass of glutamatergic neurons (i.e., zincergic neurons), and serves as a signal factor (Zn²⁺ signal) in the intracellular (cytosol) compartment as well as in the extracellular compartment. Zn²⁺ signaling is dynamically linked to glutamate signaling and may be involved in synaptic plasticity, such as long‐term potentiaion and cognitive activity. In zincergic synapses, intracellular Zn²⁺ signaling in the postsynaptic neurons, which is linked to Zn²⁺ release from zincergic neuron terminals, plays a role in cognitive activity. When nonzincergic synapses participate in cognition, on the other hand, it is possible that intracellular Zn²⁺ signaling, which is due mainly to Zn²⁺ release from the internal stores and/or metallothioneins, also is involved in cognitive activity, because zinc‐dependent system such as zinc‐binding proteins is usually required for cognitive process. Intracellular Zn²⁺ dynamics may be modified via an endocrine system activity, glucocorticoid secretion in both zincergic and nonzincergic neurons, which is linked to a long‐lasting change in synaptic efficacy. On the basis of the evidence of cognitive decline caused by the lack and/or the blockade of synaptic Zn²⁺ signaling, this article summarizes the involvement of intracellular Zn²⁺ signaling in zincergic synapses in cognition and a hypothetical involvement of that in nonzincergic synapses. © 2014 Wiley Periodicals, Inc.