title: Zinc signaling in the hippocampus and its relation to pathogenesis of depression.
abstract: Histochemically reactive zinc (Zn(2+)) is co-released with glutamate from zincergic neurons, a subclass of glutamatergic neurons. Zn(2+) 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 Zn(2+) in stress-induced attenuation of CA1 LTP was examined in hippocampal slices from young rats after exposure to tail suspension stress for 30s, 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 Zn(2+) by clioquinol participates in this amelioration. To pursue the involvement of corticosterone-mediated Zn(2+) signal in the attenuated CA1 LTP by stress, dynamics of synaptic Zn(2+) was checked in hippocampal slices exposed to corticosterone. Corticosterone increased extracellular Zn(2+) levels measured with ZnAF-2 dose-dependently, as well as the intracellular Ca(2+) levels measured with calcium orange AM, suggesting that corticosterone excites zincergic neurons in the hippocampus and increases Zn(2+) release from the neuron terminals. Intracellular Zn(2+) 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 Zn(2+) levels is increased by the influx of extracellular Zn(2+). Furthermore, corticosterone-induced attenuation of CA1 LTP was abolished in the coexistence of CaEDTA. The present study suggests that corticosterone-mediated increase in postsynaptic Zn(2+) 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 Zn(2+) 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.
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Global COE-21, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. takedaa@u-shizuoka-ken.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takeda
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000494:pharmacology; D003863:Depression / Q000378:metabolism* / Q000473:pathology*; D005938:Glucocorticoids / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D013312:Stress, Physiological / Q000502:physiology; D015032:Zinc / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D015032:Zinc; D003345:Corticosterone