Corticosteroid receptor-mediated synaptic Zn²⁺ dynamics in the hippocampus and its significance

Abstract

Neuronal Zn²⁺ homeostasis is closely linked with not only cognitive function but also cognitive decline, while there is no hormone involved in zinc homeostasis unlike calcium homeostasis. Extracellular Zn²⁺ dynamics is modified by extracellular levels of glucocorticoids and glutamate, which are linked with stress response. Extracellular glucocorticoid signal is transmitted via not only glucocorticoid receptors but also mineralocorticoid receptors. Membrane corticosteroid receptors dynamically modifies synaptic Zn²⁺ dynamics in the hippocampus. Synaptic plasticity, i.e., long-term potentiation (LTP), which is a cellular mechanism of memory, is affected by rapid intracellular Zn²⁺ dysregulation via membrane corticosteroid receptor activation in the CA1; Corticosterone rapidly induces the increase in intracellular Zn²⁺ via membrane corticosteroid receptor activation, and decreases phosphorylated CaMKII level, resulting in attenuating CA1 LTP. The mechanism of intracellular Zn²⁺ dysregulation is different between membrane mineralocorticoid and glucocorticoid receptor-mediated signaling. In contrast, corticosterone-induced intracellular Ca²⁺ dysregulation is less crucial for affecting CA1 LTP. The basal concentration (~100 pM) of intracellular Zn²⁺ is much lower than that (~100 nM) of intracellular Ca²⁺. Therefore, the precise mechanism is required to regulate intracellular Zn²⁺ homeostasis because of more critical neurotoxicity of Zn²⁺. This review summarizes the physiological significance of intracellular Zn²⁺ homeostasis focused on signaling of corticosterone and glutamate in the extracellular compartment.

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