Inhibitory function of zinc against excitation of hippocampal glutamatergic neurons

J of Neuroscience Research

Fuke

Minami

et al. 2007

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The uptake of free zinc into CA3 pyramidal cells and its significance was examined in rat hippocampal slices with ZnAF-2DA, a membrane-permeable zinc indicator. Intracellular ZnAF-2 signal in the CA3 pyramidal cell layer was increased during delivery of tetanic stimuli to the dentate granule cell layer. This increase was completely blocked in the presence of CNQX, an AMPA/kainate receptor antagonist. These results suggest that free zinc is taken up into CA3 pyramidal cells via activation of AMPA/kainate receptors. The effect of free zinc levels in the CA3 pyramidal cells on the increase in intracellular calcium via Group I metabotropic glutamate receptors was examined by regional delivery of tADA, a Group I metabotropic glutamate receptor agonist, to the stratum lucidum after blockade of AMPA/kainate receptor-mediated calcium and zinc influx. Intracellular calcium orange signal in the CA3 pyramidal cell layer was increased by tADA, whereas intracellular ZnAF-2 signal was not increased even in the presence of 100 muM zinc, suggesting that tADA induces calcium release from internal stores in CA3 pyramidal cells and is not involved in zinc uptake. The increase in calcium orange signal by tADA was enhanced by perfusion with pyrithione, a zinc ionophore that decreased basal ZnAF-2 signal in the CA3 pyramidal cell layer. It was blocked by perfusion with pyrithione and zinc that increased basal ZnAF-2 signal. The present study indicates that the increase in free calcium levels via the metabotropic glutamate receptor pathway is inversely related to free zinc levels in CA3 pyramidal cells.

Section: Discussionmentioning

confidence: 96%

Role of zinc influx via AMPA/kainate receptor activation in metabotropic glutamate receptor‐mediated calcium release

J of Neuroscience Research

Fuke

Minami

et al. 2007

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“…Therefore, it is likely that Schaffer collateral zinc protects CA1 neurons from hyperexcitation via excessive input to CA3 pyramidal cells. Zinc increases extracellular g-aminobutyric acid (GABA) levels in the hippocampus (Takeda et al, 2003). This increase seems to be associated with inhibition of GABA transporter 4, which is extensively expressed in the hippocampus (Cohen-Kfir et al, 2005).…”

Section: Zinc Action Against Intracellular Calcium Signal After Stimumentioning

confidence: 99%

Negative modulation of presynaptic activity by zinc released from schaffer collaterals

J of Neuroscience Research

Fuke

Tsutsumi

et al. 2007

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The role of zinc in excitation of Schaffer collateral-CA1 pyramidal cell synapses is poorly understood. Schaffer collaterals stained with ZnAF-2 or ZnAF-2DA, a membrane-impermeable or a membrane-permeable zinc indicator, respectively, were treated by tetanic stimulation (200 Hz, 1 sec). Extracellular and intracellular ZnAF-2 signals were increased in the stratum radiatum of the CA1, in which Schaffer collateral synapses exist. Both the increases were completely blocked in the presence of 1 mM CaEDAT, a membrane-impermeable zinc chelator, suggesting that 1 mM CaEDTA is effective for chelating zinc released from Schaffer collaterals. The role of Schaffer collateral zinc in presynaptic activity was examined by using FM4-64, a fluorescent indicator for vesicular exocytosis. The decrease in FM4-64 signal during tetanic stimulation (10 Hz, 180 sec) was enhanced in Schaffer collaterals in the presence of 1 mM CaEDTA but suppressed in the presence of 5 microM ZnC1(2), suggesting that zinc released from Schaffer collaterals suppresses presynaptic activity during tetanic stimulation. When Schaffer collateral synapses stained with calcium orange AM, a membrane-permeable calcium indicator, were regionally stimulated with 1 mM glutamate, calcium orange signal was increased in the CA1 pyramidal cell layer. This increase was enhanced in the presence of CaEDTA and attenuated in the presence of zinc. These results suggest that zinc attenuates excitation of Schaffer collateral synapses elicited with glutamate via suppression of presynaptic activity.

“…40) Because the extracellular glutamate concentration was decreased by perfusion with zinc in the CA1 region, zinc action in the postsynaptic response (glutamate release) was studied using the CA1-entorhinal connection. 41) Perfusion of the CA1 with tetrodotoxin 1 µM, a sodium channel blocker, significantly decreased the extracellular glutamate concentration in the entorhinal cortex, while perfusion of the CA1 with glutamate 50 µM significantly increased it, indicating that the response of postsynaptic CA1 pyramidal cells can be monitored by the level of glutamate released from the neuron terminals in the entorhinal cortex. When the CA1 region was perfused with zinc 50 µM, the glutamate concentration was decreased not only in the CA1 but also in the entorhinal cortex.…”

Section: )mentioning

confidence: 99%

Analysis of Brain Function and Prevention of Brain Diseases: the Action of Trace Metals

JOURNAL OF HEALTH SCIENCE

2004

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Trace metals such as zinc, manganese, and iron are necessary for the growth and function of the brain. The transport of trace metals into the brain is strictly regulated by the brain barrier system, i.e., the blood-brain and blood-cerebrospinal fluid barriers. The alteration of homeostasis of trace metals in the brain is associated with brain diseases. Trace metals usually serve the function of metalloproteins in neurons and glial cells, while a portion of trace metals exists in the presynaptic vesicles and may be released with neurotransmitters into the synaptic cleft. Zinc and manganese influence the concentration of neurotransmitters in the synaptic cleft, probably via the action against neurotransmitter receptors and transporters and ion channels. Zinc may be an inhibitory neuromodulator of glutamate release in the hippocampus, while neuromodulation by manganese might have both functional and toxic aspects in the synapse. Dietary zinc deficiency affects zinc homeostasis in the brain, followed by an enhanced excitotoxicity of glutamate in the hippocampus. Transferrin may be involved in the physiologic transport of iron and manganese into the brain and their utilization there.