Involvement of glucocorticoid-mediated Zn2+ signaling in attenuation of hippocampal CA1 LTP by acute stress
Highlights
► Clioquinol ameliorates stress-induced attenuation of CA1 LTP. ► Corticosterone increases Zn2+ release from zincergic neuron. ► Corticosterone also increases cytosolic Zn2+ by zincergic excitation. ► CaEDTA abolishes corticosterone-induced attenuation of CA1 LTP. ► Increase in cytosolic Zn2+ is involved in attenuation of CA1 LTP by stress.
Introduction
Stress disturbs physiological and psychological homeostasis of humans and animals (Lee et al., 2002). Stress activates the hypothalamo-pituitary-adrenocortical (HPA) system, increases glucocorticoid secretion from the adrenal cortex, and affects learning and memory processes. The hippocampus participates in cognitive function and also plays an important role in stress response. Hippocampal neurons are enriched with glucocorticoid receptors, in addition to mineralocorticoid receptors and negatively modulate the HPA system activity (Kim and Yoon, 1998). However, the hippocampus is vulnerable to stress (McEwen, 1999, Garcia, 2001, Kim et al., 2006).
Stress and glucocorticoids have diverse effects on synaptic plasticity such as long-term potentiation (LTP) that is thought to be the cellular mechanism of memory (Wong et al., 2007, Howland and Wang, 2008). The mechanisms of the diverse effects are poorly understood. Glucocorticoid–glutamatergic interactions during information processing are proposed as a potential model to explain many of the diverse effects of glucocorticoids on cognition (Sandi, 2011). Glucocorticoids can affect glutamatergic pathways through the increase in extracellular glutamate. An increase in serum corticosterone level produces a rapid increase in corticosterone level in the hippocampus in parallel with a specific increase in extracellular glutamate level (Venero and Borrell, 1999, Droste et al., 2008). In the hippocampus, corticosterone-induced increase in extracellular glutamate can be exerted through a variety of mechanisms, including glucocorticoid receptor-mediated inhibition of glutamate uptake (Virgin et al., 1991, Yang et al., 2005) and membrane mineralocorticoid receptor- or/and glucocorticoid receptor-mediated increase of presynaptic glutamate release probability (Karst et al., 2005, Olijslagers et al., 2008, Wang and Wang, 2009).
Histochemically reactive (chelatable) zinc (Zn2+) is co-released with glutamate from zincergic neurons, a subclass of glutamatergic neurons and serves as a signal factor (Zn2+ signal) in both the extracellular and intracellular compartments (Frederickson et al., 2005, Takeda and Tamano, 2009). Thus, it is possible that presynaptic release probability of glutamate and zinc is increased by corticosterone in the hippocampus. However, there is no report on glucocorticoid–zincergic interactions in the hippocampus. It is important to study the involvement of glucocorticoid–zincergic interactions in stress-induced impairment of synaptic plasticity and memory, because corticosterone potentially excites zincergic neurons and releases Zn2+ from the neuron terminals (Takeda and Tamano, 2010). This idea is supported by the data on dynamics of synaptic Zn2+ in the hippocampus after exposure to stress. Restraint stress increases glutamate and zinc in the extracellular fluid of the hippocampus. In contrast, in the cases of exposure to novelty stress (Takeda et al., 2006, Takeda et al., 2009a) and tail suspension stress for a short period (Takeda et al., 2009b), extracellular zinc is decreased, in spite of the increase in extracellular glutamate. The decrease in extracellular zinc is estimated to be due to the increase in zinc influx into neuronal and glial cells. Serum zinc level is decreased after exposure to acute stress and this decrease may be associated with corticosterone-mediated synthesis of metallothioneins in the tissues, especially in the liver (Cousins, 1986, Cousins et al., 1986, Tamano et al., 2000). It is possible that psychological stress facilitates cellular zinc influx through the action of corticosterone and that physical stress, i.e., restraint stress, induces more increases in corticosterone secretion, which might lead to excess of extracellular zinc.
In the present study, the involvement of synaptic Zn2+ in stress-induced attenuation of hippocampal CA1 LTP was examined by using clioquinol (5-chloro-7-iodo-8-hydroxyquinoline), a membrane-permeable zinc chelator. Clioquinol has a relatively weak affinity for zinc (Kd, approximately 1 × 10−7 M) and can reduce synaptic Zn2+ (Cherny et al., 2001). On the basis of the data that clioquinol ameliorated stress-induced attenuation of CA1 LTP, the present study also evaluates corticosterone-mediated dynamics of synaptic Zn2+ and its significance in the attenuated CA1 LTP.
Section snippets
Animals
Male Wistar rats (6-week-old) were purchased from Japan SLC (Hamamatsu, Japan). They were housed under the standard laboratory conditions (23 ± 1 °C, 55 ± 5% humidity) and had access to tap water and food ad libitum. The lights were automatically turned on at 8:00 and off at 20:00. Some days later, rats were used for experiments. All experiments were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of the University of Shizuoka that refer to American Association
Ameliorative effect of zinc chelator on stress-induced attenuation of CA1 LTP
Tail suspension stress for 30 s significantly increased serum corticosterone level (control, 66.6 ± 17.5 ng/ml; stress, 209.0 ± 45.5%; p < 0.05 vs. control; Fig. 1). To examine the influence of tail suspension in the induction of CA1 LTP, hippocampal slices were prepared from rats 1 h after exposure to tail suspension for 30 s. CA1 LTP induced by tetanic stimulation (100 Hz, 1 s) was significantly attenuated (control, 152.7 ± 6.8%; stress, 131.5 ± 5.2%; p < 0.05 vs. control; Fig. 2). This LTP was completely
Discussion
CA1 LTP consists of NMDA receptor-dependent and NMDA receptor-independent components (Grover and Teyler, 1990, Cavuş and Teyler, 1996). The induction of NMDA receptor-dependent CA1 LTP is more vulnerable to stress than that of NMDA receptor-independent CA1 LTP (Kim et al., 1996, Wiegert et al., 2005, Joëls and Krugers, 2007). In the present study, 100-Hz tetanus-induced LTP, which was NMDA receptor-dependent, was attenuated by tail suspension stress for 30 s. When clioquinol was injected to
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