Zinc signaling in the hippocampus and its relation to pathogenesis of depression

Histochemically reactive zinc (Zn2+) is co-released with glutamate from zincergic neurons, a subclass of glutamatergic neurons. Zn2+ serves as a signal factor in both the extracellular and intracellular compartments. Glucocorticoid–glutamatergic interactions have been proposed as a potential model to explain stress-mediated impairment of hippocampal function, i.e., cognition. However, it is unknown whether glucocorticoid–zincergic interactions are involved in this impairment. In the present study, involvement of synaptic Zn2+ in stress-induced attenuation of CA1 LTP was examined in hippocampal slices from young rats after exposure to tail suspension stress for 30 s, which significantly increased serum corticosterone. Stress-induced attenuation of CA1 LTP was ameliorated by administration of clioquinol, a membrane permeable zinc chelator, to rats prior to exposure to stress, implying that the reduction of synaptic Zn2+ by clioquinol participates in this amelioration. To pursue the involvement of corticosterone-mediated Zn2+ signal in the attenuated CA1 LTP by stress, dynamics of synaptic Zn2+ was checked in hippocampal slices exposed to corticosterone. Corticosterone increased extracellular Zn2+ levels measured with ZnAF-2 dose-dependently, as well as the intracellular Ca2+ levels measured with calcium orange AM, suggesting that corticosterone excites zincergic neurons in the hippocampus and increases Zn2+ release from the neuron terminals. Intracellular Zn2+ levels measured with ZnAF-2DA were also increased dose-dependently, but not in the coexistence of CaEDTA, a membrane-impermeable zinc chelator, suggesting that intracellular Zn2+ levels is increased by the influx of extracellular Zn2+. Furthermore, corticosterone-induced attenuation of CA1 LTP was abolished in the coexistence of CaEDTA. The present study suggests that corticosterone-mediated increase in postsynaptic Zn2+ signal in the cytosolic compartment is involved in the attenuation of CA1 LTP after exposure to acute stress. We propose that corticosterone-mediated increase in postsynaptic Zn2+ signal, which is induced by acute stress, changes hippocampal function and then is possibly a risk factor under chronic stress circumstances to induce depressive symptoms.