| | Abnormal Ca2+ mobilization in hippocampal slices of epileptic animals fed a zinc-deficient dietReceived 12 May 2008; received in revised form 24 September 2008; accepted 25 September 2008. Summary On the basis of the evidence of the enhanced susceptibility to kainate-induced seizures in zinc-deficient mice and rats, the mechanism of the enhanced susceptibility was examined focused on neuronal Ca2+ mobilization. Brain slices were prepared from rats fed a zinc-deficient diet for 4 weeks. Intracellular fura-2 signals in the hippocampal CA3, in which the basal fura-2 signals were higher in zinc deficiency, were significantly more increased 4 s after delivery of kainate (1mM/1μl, 1s) to the dentate granule cell layer. Calcium orange signal in mossy fiber boutons was also significantly more increased in zinc deficiency after delivery of tetanic stimuli (100Hz, 5s) to the dentate granule cell layer in the presence of CNQX, a blocker of AMPA/kainate receptors. The decrease in FM4-64 signal, a direct measure of vesicular exocytosis, in mossy fiber boutons during tetanic stimulation (10Hz, 180s) was significantly enhanced in zinc deficiency. These results indicate that intracellular Ca2+ mobilization in the hippocampus is affected in zinc deficiency, followed by the enhancement of exocytosis at mossy fiber boutons. In NMDA-challenged mice, which were fed the zinc-deficient diet for 4 weeks, furthermore, seizure susceptibility was significantly enhanced. It is likely that abnormal Ca2+ mobilization in neurons is involved in seizure susceptibility in zinc-deficient animals. Introduction  Zinc acts either as an anticonvulsant (Williamson and Spencer, 1995) or a proconvulsant (Pei et al., 1983). Zinc homeostasis in the brain is associated with the etiology and manifestation of epileptic seizures (Sterman et al., 1988, Buhl et al., 1996). Seizure susceptibility of EL (epilepsy) mice is attenuated by dietary zinc loading, while it is enhanced by dietary zinc deficiency (Fukahori and Itoh, 1990). Susceptibility to kindled seizures is also attenuated by dietary zinc loading, while this susceptibility in cats is enhanced by zinc deficiency (Sterman et al., 1986). These findings suggest that susceptibility to epileptic seizures is enhanced by zinc deficiency. However, the mechanism of the enhanced seizure susceptibility in zinc deficiency is unknown. In temporal lobe epilepsy, seizures frequently originate in the hippocampus and then spread to other brain regions (Seyfried and Glaser, 1985). The increase in extracellular glutamate in the hippocampus may trigger spontaneous seizures in patients with complex partial epilepsy (During and Spencer, 1993). Although zinc homeostasis in the brain is not easily affected by dietary zinc deficiency (Takeda, 2001), the hippocampus seems to be vulnerable to zinc deficiency. Zinc concentration in the hippocampus (approximately 300μM), which is relatively high in the brain, is decreased in zinc-deficient young mice and rats (Takeda et al., 2001, Takeda et al., 2005b). The hippocampus possesses zinc-containing glutamatergic neurons that sequester zinc in the presynaptic vesicles and release it in a calcium- and impulse-dependent manner (Frederickson, 1989, Frederickson and Danscher, 1990). All giant boutons of mossy fibers contain zinc in the presynaptic vesicles (Sindreu et al., 2003). Vesicular zinc is histochemically reactive as revealed by Timm's sulfide-silver staining and serves as an endogenous neuromodulator (Xie and Smart, 1991). Zinc inhibits NMDA receptors (Westbrook and Mayer, 1987), while it potentiates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors (Rassendren et al., 1990). In the hippocampus, zinc negatively modulates calcium mobilization in glutamatergic neurons (Quinta-Ferreira and Matias, 2004, Quinta-Ferreira and Matias, 2005) and may serve as a negative feedback factor for glutamate release (Bancila et al., 2004, Minami et al., 2006, Takeda et al., 2007a). Zinc also increases the concentration of extracellular GABA (Takeda et al., 2004) and may suppress excess excitation of mossy fiber synapses (Takeda et al., 2007b). However, excessive zinc release from mossy fibers is neurotoxic to postsynaptic neurons (Koh et al., 1996, Choi and Koh, 1998, Lee et al., 1999, Weiss et al., 2000, Suh et al., 2004). Côté et al. (2005) report that the neurotoxic and neuroprotective actions of zinc depend on its concentration and that this dual action is cell type specific. Zinc concentration in the synaptic vesicles, in addition to that in the extracellular fluid, is decreased in young mice and rats after 4-week zinc deprivation (Takeda, 2004, Takeda et al., 2003a, Takeda et al., 2003b). Synaptic zinc is responsive to dietary zinc deficiency. It is possible that the decrease in synaptic zinc elicits imbalance of synaptic inhibition–excitation. On the other hand, zinc is necessary for many enzymes and cellular processes including gene expression, which might be compromised in zinc deficiency (Prasad, 1988, Vallee and Falchuk, 1993). Thus, neuronal dysfunction elicited by zinc deficiency is very complicated. Dietary zinc deficiency causes anorexia, reduced gain in the body weight and growth retardation (Golub et al., 1995). It activates the hypothalamic–pituitary–adrenal (HPA) axis, followed by the increase in glucocorticoid secretion from the adrenal (Chu et al., 2003). Glucocorticoids increase cytosolic Ca2+ concentration in cultured hippocampal neurons (Elliott and Sapolsky, 1992, Elliott and Sapolsky, 1993), implying that the increase in glucocorticoid secretion influences glutamatergic neuron activity. On the basis of the data that intracellular Ca2+ homeostasis is affected by zinc deficiency (Takeda et al., 2005b), in the present study, the mechanism of the enhanced susceptibility to kainate-induced seizures in zinc deficiency (Takeda et al., 2003a, Takeda et al., 2005a) was checked focused on Ca2+ mobilization at mossy fiber synapses. Under both physiological and pathological condition, activation of NMDA receptors plays a key role for postsynaptic excitation via Ca2+ influx. Thus, seizures susceptibility was checked in NMDA-challenged zinc-deficient mice. Materials and methods Intracellular calcium signal after stimulation with kainate Fura-2 AM and calcium orange AM, membrane-permeable calcium indicators, and FM4-64, an indicator of presynaptic activity, were purchased from Molecular Probes, Inc. (Eugene, OR) and SIGMA (St. Louis, MO), respectively. ZnAF-2DA, a membrane-permeable zinc indicator, was kindly supplied from Daiichi Pure Chemicals Co., Ltd. (Tokyo, Japan). These fluorescent indicators were dissolved in dimethyl sulfoxide (DMSO) and then diluted with artificial cerebrospinal fluid (ACSF), which was composed of 124mM NaCl, 2.5mM KCl, 2.0mM CaCl2, 1.0mM MgCl2, 1.25mM NaH2PO4, 26mM NaHCO3 and 10mM d-glucose (pH 7.3). To facilitate cellular uptake of membrane-permeable indicators, cremophore EL (Sigma) was added to DMSO solutions (the final concentration, 0.02%). The brain slices were put in ACSF (2ml) containing 10μM fura-2 AM in the dark for 45min at 25°C. To remove unincorporated fura-2 AM in the extracellular fluid, the slices were put in ACSF (100ml) in the dark at 25°C, transferred to a chamber for observation filled with ACSF (2ml) and mounted on the stage of an inverted microscope (Diaphot TMD 300, Nikon, Tokyo, Japan). Fluorescence intensity was measured in the hippocampal CA3 by an Argus-50/CA system (Hamamatsu Photonics, Hamamatsu, Japan; excitation, 340nm; dichroic beam splitter, 505nm) at 25°C. The dentate granular cell layer was stimulated with 1μl of 1mM kainate via a microdialysis probe without membrane at a flow rate of 1μl/s by using a microinjection pump (CMA/100, CMA Microdialysis), at a given time after the start of measuring the basal fura-2 signals. The change in fura-2 signals was monitored in the stratum radiatum, stratum lucidum and CA3 pyramidal cell layer by the Argus-50/CA system. Region of interest was set in the three regions as shown in Fig. 1A (11 slices from three control rats and 11 slices from three zinc-deficient rats). Presynaptic calcium signal after electrical stimulation To image intracellular zinc and calcium, the brain slices were loaded with 10μM ZnAF-2DA and 10μM calcium orange AM for 30min and then transferred a chamber filled with ACSF to wash out unincorporated extracellular ZnAF-2DA and calcium orange AM for at least 30min. The brain slices were transferred to a recording chamber filled with 10μM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of AMPA/kainate receptors, in ACSF (3ml). The fluorescence of ZnAF-2 (excitation, 488nm; monitoring, 505–530nm) and calcium orange (excitation, 543nm; monitoring, above 560nm) was measured in the hippocampal CA3 with a confocal laser-scanning microscopic system LSM 510 META (Carl Zeiss), equipped with the inverted microscope (Axiovert 200M, Carl Zeiss). ZnAF-2DA was used to identify mossy fiber synapses. Electrical stimuli (100Hz, 5s, 100μA, 200μs/pulse) were delivered to the dentate granule cell layer through a tungsten electrode at a given time after the start of measuring the basal calcium orange signals. The change in calcium orange signals was measured in the mossy fiber synapses by using the confocal laser-scanning microscopic system LSM 510 META at the rate of 1Hz through a 20× objective. Region of interest was set at mossy fiber synapses as shown in Fig. 2A (12 slices from three control rats and 12 slices from three zinc-deficient rats). Exocytosis with FM4-64 The brain slices, which were prepared from the control and zinc-deficient rats, were transferred to an incubation chamber filled with ACSF containing 10μM ZnAF-2DA, allowed to stand at 25°C for 30min, transferred a chamber filled with ACSF to wash out extracellular ZnAF-2DA for at least 30min, transferred to an incubation chamber filled with ACSF containing 5μM FM4-64 and 45mM KCl, allowed to stand at 25°C for 90s, transferred a chamber filled with ACSF to wash out extracellular FM4-64 and transferred to a recording chamber filled with ACSF containing 10μM CNQX. The fluorescence of FM 4-64 (excitation, 488nm; monitoring, above 650nm) and ZnAF-2 was measured with the confocal laser-scanning microscopic system LSM 510 META at the rate of 1Hz through a 20× objective. Fifty seconds later, electrical stimuli (10Hz, 180s, 100μA, 200μs/pulse) were delivered to the dentate granular cell layer through a tungsten electrode. Attenuation of FM 4-64 fluorescence (destaining) by presynaptic activity was measured with the confocal laser-scanning microscopic system LSM 510 META in the same manner. At the end of the experiments, complete depolarization-induced destaining was evoked by single strong stimuli (100Hz, 18s, 100μA, 200μs/pulse). Region of interest was set at mossy fiber synapses double-labeled with FM4-64 and ZnAF-2 as shown in Fig. 3A. The activity-dependent component of FM4-64 fluorescence in the mossy fiber boutons was measured for each punctum by subtracting its residual fluorescence intensity (<10% of initial intensity) measured after the strong electrical stimulation that produced maximal destaining. FM4-64 signal was then normalized by the maximal fluorescence intensity before the electrical stimulation (7 slices from three control rats and 7 slices from three zinc-deficient rats). Seizure induction Mice were fed the control and zinc-deficient diet for 4 weeks and then intraperitoneally injected with NMDA (150mg/kg body weight). The behavior of mice was recorded for 2h with a video camera and seizure scores were taken according to the procedure reported previously (10 control and 10 zinc-deficient mice) (Cruz et al., 2003, Marganella et al., 2005). Statistical analysis Student's t-test was used for comparison of the means of unpaired data. For multiple comparison ANOVA followed by Fisher's protected least significant difference (PLSD) was performed. Results Calcium signal in the hippocampal CA3 The basal Ca2+ levels monitored with fura-2 are significantly higher in the hippocampal CA3 of brain slices prepared from zinc-deficient mice than in the control (Takeda et al., 2005b). The basal Ca2+ levels in the hippocampal CA3 were also higher in brain slices from rats, which were fed a zinc-deficient diet for 4 weeks (8 weeks old, mean body weight: control, 204g; zinc-deficient, 105g) (Fig. 1A). To examine abnormal Ca2+ mobilization in zinc deficiency, furthermore, kainate (1mM, 1μl) was delivered for 1s to the dentate granule cell layer (Fig. 1B). Fura-2 signals in the hippocampal CA3 were increased in both slices. Fura-2 signals in the three regions were significantly more increased in zinc-deficient slices 4s after the stimulation. To check the increase in Ca2+ levels in mossy fiber boutons after depolarization, tetanic stimuli at 100Hz for 5s were delivered to the dentate granule cell layer in the presence of CNQX. Calcium orange signal was monitored at mossy fiber synapses double-stained with ZnAF-2DA and calcium orange AM (Fig. 2A). Because CNQX completely blocks the increase in calcium orange signal in postsynaptic pyramidal cells during tetanic stimulation (100Hz, 5s) (Takeda et al., 2007a), the increase in calcium orange signal in mossy fiber synapses may originate from mossy fiber boutons. Calcium orange signal was increased in mossy fiber boutons after tetanic stimulation in both slices and was significantly more increased in zinc-deficient slices (Fig. 2B). Exocytosis at mossy fiber boutons It is possible that the abnormal increase in Ca2+ levels in mossy fiber boutons after depolarization enhances mossy fiber activity. To pursue this possibility, exocytosis was evaluated using a fluorescent styryl dye FM4-64. FM4-64 is taken up into presynaptic vesicles in an activity-dependent manner. Subsequent rounds of exocytosis arising from depolarization lead to the release of the dye from the presynaptic terminals (destaining). Because fluorescence signal originates from vesicular membrane-bound FM4-64, FM4-64 signal is attenuated by presynaptic activity (Klingauf et al., 1998, Zakharenko et al., 2001). Tetanic stimuli at 10Hz for 180s were delivered to the dentate granule cells and the activity of mossy fibers double-stained with ZnAF-2DA and FM4-64 was evaluated by attenuation of FM4-64 signal in the presence of CNQX (Fig. 3A). Attenuation of FM4-64 signal in mossy fiber boutons was significantly enhanced by zinc deficiency (Fig. 3B). Discussion The basal Ca2+ levels in the hippocampal CA3 were elevated in brain slices from zinc-deficient rat, in agreement with the previous result obtained in brain slices from zinc-deficient mice (Takeda et al., 2005b). It is possible that the increase in glucocorticoid secretion by zinc deficiency affects intracellular Ca2+ homeostasis in the hippocampus (Elliott and Sapolsky, 1992, Elliott and Sapolsky, 1993, Lee et al., 2002). Because intracellular Ca2+ signaling is linked to neuronal excitation, the increase in the basal Ca2+ levels in zinc deficiency might influence neuronal activity in the hippocampus. On the other hand, it has been reported that the change in mossy fiber activity is linked to epileptogenesis and seizure susceptibility (Tauck and Nadler, 1985, Sutula et al., 1998, Cavazos et al., 1991, Morimoto et al., 2004). To understand the mechanism associated with seizure susceptibility in zinc deficiency, in the present study, mossy fiber activity was checked focused on Ca2+ mobilization. Intracellular Ca2+ levels in the CA3 were measured after delivery of kainate (1mM, 1μl, 1s) to the dentate granule cell layer. The increase in fura-2 signal in the stratum lucidum and other CA3 areas was enhanced by zinc deficiency, suggesting that intracellular Ca2+ mobilization after mossy fiber excitation is enhanced by zinc deficiency. Presynaptic calcium-permeable kainate receptors, which are expressed in mossy fibers in high densities, facilitate glutamate release from mossy fibers (Monaghan and Cotman, 1982, Schmitz et al., 2001, Lauri et al., 2003, Rodriguez-Moreno and Sihra, 2004). It is possible that presynaptic kainate receptors are linked to abnormal Ca2+ mobilization, followed by the facilitation of glutamate release in zinc deficiency. To pursue abnormal Ca2+ mobilization in mossy fiber boutons after depolarization, tetanic stimuli at 100Hz for 5s were delivered to the dentate granule cell layer in the presence of CNQX that completely blocks the increase in Ca2+ levels in postsynaptic pyramidal cells during tetanic stimulation (Takeda et al., 2007a). The increase in calcium orange signal in mossy fiber boutons was significantly enhanced by zinc deficiency. CNQX blocks not only postsynaptic AMPA/kainate receptors but also presynaptic kainate receptors. Thus, it is likely that voltage-dependent calcium channels are involved in abnormal Ca2+ mobilization in mossy fiber boutons after depolarization in zinc deficiency. To check mossy fiber activity associated with the abnormal Ca2+ mobilization, exocytosis was measured during delivery of tetanic stimuli at 100Hz for 180s to the dentate granule cell layer in the presence of CNQX. Exocytosis at mossy fiber boutons was significantly enhanced by zinc deficiency. These results indicate that intracellular Ca2+ mobilization in the hippocampus is affected in zinc deficiency, followed by the enhancement of exocytosis at mossy fiber boutons. Zinc transporter 3 knockout mice that lack histochemically reactive zinc in the presynaptic vesicles are more sensitive to kainate-induced seizures than the control mice, suggesting that synaptic zinc is involved in the seizure susceptibility and that the net effect of synaptic zinc on acute seizures in vivo is inhibitory (Cole et al., 2000). Quinta-Ferreira and Matias, 2004, Quinta-Ferreira and Matias, 2005 report that Ca2+ influx into mossy fibers by tetanic stimulation is inhibited by endogenous zinc. Furthermore, a sustained increase in Ca2+ levels in CA3 pyramidal neurons is enhanced in the presence of 1–10mM CaEDTA, a membrane-impermeable zinc chelator, after regional delivery of 1mM glutamate to dentate granule cells (Takeda et al., 2007b). Lavoie et al. (2007) report that intracellular zinc chelator influences hippocampal neuronal excitability in rats. Because synaptic zinc seems to be lower levels in young mice and rats after 4-week zinc deprivation (Takeda, 2004, Takeda et al., 2003a, Takeda et al., 2003b), it is possible that insufficient zinc release from mossy fibers, in spite of excessive glutamate release, is involved in the extracellular accumulation of glutamate in kainate-challenged zinc-deficient rats, followed by the enhanced seizure susceptibility (Takeda et al., 2003a). AMPA/kainate receptors activate NADA receptors and trigger the excitation of glutamatergic neurons. Zinc is an endogenous NMDA receptor antagonist (Westbrook and Mayer, 1987, Vogt et al., 2000, Molnár and Nadler, 2001). Calcium influx via NMDA receptors plays a key role for the excitation of glutamatergic neurons. It is possible that the action of zinc as a NMDA receptor antagonist weakens in zinc deficiency because of the insufficient zinc release. Because seizure activity can be induced with excessive activation of NMDA receptors, in the present study, susceptibility to NMDA-induced seizures was examined in mice fed the zinc-deficient diet for 4 weeks. NMDA-induced seizures were significantly enhanced by zinc deficiency. Ionotropic glutamate receptor agonists such as kainate and NMDA, which is directly linked to CA2+ influx, seems to aggravate the affected Ca2+ homeostasis in the hippocampus in zinc deficiency. 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Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan  Corresponding author. Tel.: +81 54 264 5700; fax: +81 54 264 5705.
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