Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Global COE-21, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
J Trace Elem Med Biol. 2012 Jun;26(2-3):80-4. doi: 10.1016/j.jtemb.2012.03.016. Epub 2012 May 5.
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.
组织化学活性锌（Zn(2+)）与谷氨酸从锌能神经元共释放，这是谷氨酸能神经元的一个亚类。Zn(2+)在细胞外和细胞内区室中均作为信号因子。糖皮质激素-谷氨酸能相互作用已被提议作为解释应激介导的海马功能损害（即认知）的潜在模型。然而，尚不清楚糖皮质激素-锌能相互作用是否参与这种损害。在本研究中，在经历 30 秒尾悬应激的年轻大鼠海马切片中，研究了突触 Zn(2+)在应激诱导的 CA1LTP 衰减中的作用，该应激显著增加了血清皮质酮。在暴露于应激之前，给大鼠施用膜通透锌螯合剂氯喹啉，可改善应激诱导的 CA1LTP 衰减，这表明氯喹啉减少突触 Zn(2+)参与了这种改善。为了研究应激诱导的 CA1LTP 衰减中皮质酮介导的 Zn(2+)信号的参与，在暴露于皮质酮的海马切片中检查了突触 Zn(2+)的动力学。皮质酮以剂量依赖性方式增加了 ZnAF-2 测量的细胞外 Zn(2+)水平，以及钙橙 AM 测量的细胞内 Ca(2+)水平，这表明皮质酮兴奋海马中的锌能神经元并增加神经元末梢的 Zn(2+)释放。ZnAF-2DA 测量的细胞内 Zn(2+)水平也以剂量依赖性方式增加，但在膜不可渗透锌螯合剂 CaEDTA 的共存下不增加，这表明细胞内 Zn(2+)水平是通过细胞外 Zn(2+)的内流增加的。此外，在 CaEDTA 共存下，皮质酮诱导的 CA1LTP 衰减被消除。本研究表明，应激后细胞溶质区室中皮质酮介导的突触后 Zn(2+)信号增加参与了 CA1LTP 的衰减。我们提出，应激诱导的突触后 Zn(2+)信号增加改变了海马功能，然后可能是慢性应激情况下引起抑郁症状的危险因素。
