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. 1995 Apr 15;484(Pt 2):447–462. doi: 10.1113/jphysiol.1995.sp020677

Zinc potentiation of neurotransmission and inhibition of background cationic conductance in rat cultured hippocampal neurones.

K Nakazawa 1, K Inoue 1, T Watano 1, S Koizumi 1, K Inoue 1
PMCID: PMC1157906  PMID: 7602537

Abstract

1. The facilitation by zinc (Zn2+) of neurotransmission and the mechanisms underlying it were electrophysiologically investigated in rat cultured hippocampal neurones using whole-cell voltage- and current-clamp techniques. 2. Under whole-cell voltage clamp with an intracellular solution containing CsCl as a major salt, inward postsynaptic currents were observed at -40 mV in a cell culture where a neuronal network had been formed. The postsynaptic currents appeared to be mediated by gamma-aminobutyric acid (GABA) because the inward currents were abolished when intracellular CsCl was replaced with caesium phosphate and they were blocked by bicuculline (10 microM), an antagonist to GABA-gated channels. The currents were, however, also blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 30 microM), an antagonist to non-NMDA glutamate-gated channels, suggesting a contribution of a glutamatergic mechanism to the generation of the currents. Zn2+ (10 and 100 microM) potentiated the postsynaptic currents. 3. In addition to the potentiation of the postsynaptic currents, Zn2+ shifted net membrane current at -60 mV in an outward direction. The current-voltage relationship obtained under various ionic conditions indicated that Zn2+ inhibits a current component which is mainly carried by extracellular Na+. 4. Under whole-cell current clamp, Zn2+ (10 microM) induced a small hyperpolarization (up to 20 mV), which was accompanied by potentiation of the postsynaptic potentials and spike potentials. Tests were carried out to examine whether changes in resting potential by different protocols mimic responses observed with Zn2+. Hyperpolarization induced by current injection through patch pipettes increased the amplitude of postsynaptic currents, but did not enhance the appearance of spike potentials. In contrast, when extracellular K+ concentration was decreased from 5 to 2.5 mM, cells were hyperpolarized and spike potentials of large amplitude appeared. 5. The results suggest that Zn2+ potentiates neurotransmission and inhibits a background cationic current mainly carried by extracellular Na+ under physiological conditions. The inhibition of the Na+ permeation may increase membrane excitability and thereby contribute to the potentiation of neurotransmission.

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Selected References

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  1. Akaike N., Kostyuk P. G., Osipchuk Y. V. Dihydropyridine-sensitive low-threshold calcium channels in isolated rat hypothalamic neurones. J Physiol. 1989 May;412:181–195. doi: 10.1113/jphysiol.1989.sp017610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Assaf S. Y., Chung S. H. Release of endogenous Zn2+ from brain tissue during activity. Nature. 1984 Apr 19;308(5961):734–736. doi: 10.1038/308734a0. [DOI] [PubMed] [Google Scholar]
  3. Büsselberg D., Michael D., Evans M. L., Carpenter D. O., Haas H. L. Zinc (Zn2+) blocks voltage gated calcium channels in cultured rat dorsal root ganglion cells. Brain Res. 1992 Oct 9;593(1):77–81. doi: 10.1016/0006-8993(92)91266-h. [DOI] [PubMed] [Google Scholar]
  4. Celentano J. J., Gyenes M., Gibbs T. T., Farb D. H. Negative modulation of the gamma-aminobutyric acid response by extracellular zinc. Mol Pharmacol. 1991 Nov;40(5):766–773. [PubMed] [Google Scholar]
  5. Crawford I. L., Connor J. D. Zinc in maturing rat brain: hippocampal concentration and localization. J Neurochem. 1972 Jun;19(6):1451–1458. doi: 10.1111/j.1471-4159.1972.tb05088.x. [DOI] [PubMed] [Google Scholar]
  6. Draguhn A., Verdorn T. A., Ewert M., Seeburg P. H., Sakmann B. Functional and molecular distinction between recombinant rat GABAA receptor subtypes by Zn2+. Neuron. 1990 Dec;5(6):781–788. doi: 10.1016/0896-6273(90)90337-f. [DOI] [PubMed] [Google Scholar]
  7. Ficker E., Heinemann U. Slow and fast transient potassium currents in cultured rat hippocampal cells. J Physiol. 1992 Jan;445:431–455. doi: 10.1113/jphysiol.1992.sp018932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Frederickson C. J. Neurobiology of zinc and zinc-containing neurons. Int Rev Neurobiol. 1989;31:145–238. doi: 10.1016/s0074-7742(08)60279-2. [DOI] [PubMed] [Google Scholar]
  9. Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
  10. Harrison N. L., Radke H. K., Talukder G., Ffrench-Mullen J. M. Zinc modulates transient outward current gating in hippocampal neurons. Receptors Channels. 1993;1(2):153–163. [PubMed] [Google Scholar]
  11. Harrison N. L., Radke H. K., Tamkun M. M., Lovinger D. M. Modulation of gating of cloned rat and human K+ channels by micromolar Zn2+. Mol Pharmacol. 1993 Mar;43(3):482–486. [PubMed] [Google Scholar]
  12. Howell G. A., Welch M. G., Frederickson C. J. Stimulation-induced uptake and release of zinc in hippocampal slices. Nature. 1984 Apr 19;308(5961):736–738. doi: 10.1038/308736a0. [DOI] [PubMed] [Google Scholar]
  13. Huang R. C., Peng Y. W., Yau K. W. Zinc modulation of a transient potassium current and histochemical localization of the metal in neurons of the suprachiasmatic nucleus. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11806–11810. doi: 10.1073/pnas.90.24.11806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Inoue K., Nakazawa K., Fujimori K., Watano T., Takanaka A. Extracellular adenosine 5'-triphosphate-evoked glutamate release in cultured hippocampal neurons. Neurosci Lett. 1992 Jan 6;134(2):215–218. doi: 10.1016/0304-3940(92)90520-h. [DOI] [PubMed] [Google Scholar]
  15. Lansman J. B., Hess P., Tsien R. W. Blockade of current through single calcium channels by Cd2+, Mg2+, and Ca2+. Voltage and concentration dependence of calcium entry into the pore. J Gen Physiol. 1986 Sep;88(3):321–347. doi: 10.1085/jgp.88.3.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Legendre P., Westbrook G. L. Noncompetitive inhibition of gamma-aminobutyric acidA channels by Zn. Mol Pharmacol. 1991 Mar;39(3):267–274. [PubMed] [Google Scholar]
  17. Malgaroli A., Tsien R. W. Glutamate-induced long-term potentiation of the frequency of miniature synaptic currents in cultured hippocampal neurons. Nature. 1992 May 14;357(6374):134–139. doi: 10.1038/357134a0. [DOI] [PubMed] [Google Scholar]
  18. Monaghan D. T., Bridges R. J., Cotman C. W. The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system. Annu Rev Pharmacol Toxicol. 1989;29:365–402. doi: 10.1146/annurev.pa.29.040189.002053. [DOI] [PubMed] [Google Scholar]
  19. Nakazawa K., Fujimori K., Takanaka A., Inoue K. An ATP-activated conductance in pheochromocytoma cells and its suppression by extracellular calcium. J Physiol. 1990 Sep;428:257–272. doi: 10.1113/jphysiol.1990.sp018211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Peters S., Koh J., Choi D. W. Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons. Science. 1987 May 1;236(4801):589–593. doi: 10.1126/science.2883728. [DOI] [PubMed] [Google Scholar]
  21. Rassendren F. A., Lory P., Pin J. P., Nargeot J. Zinc has opposite effects on NMDA and non-NMDA receptors expressed in Xenopus oocytes. Neuron. 1990 May;4(5):733–740. doi: 10.1016/0896-6273(90)90199-p. [DOI] [PubMed] [Google Scholar]
  22. Ravindran A., Schild L., Moczydlowski E. Divalent cation selectivity for external block of voltage-dependent Na+ channels prolonged by batrachotoxin. Zn2+ induces discrete substates in cardiac Na+ channels. J Gen Physiol. 1991 Jan;97(1):89–115. doi: 10.1085/jgp.97.1.89. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Smart T. G. A novel modulatory binding site for zinc on the GABAA receptor complex in cultured rat neurones. J Physiol. 1992 Feb;447:587–625. doi: 10.1113/jphysiol.1992.sp019020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Smart T. G., Moss S. J., Xie X., Huganir R. L. GABAA receptors are differentially sensitive to zinc: dependence on subunit composition. Br J Pharmacol. 1991 Aug;103(4):1837–1839. doi: 10.1111/j.1476-5381.1991.tb12337.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Stafstrom C. E., Schwindt P. C., Chubb M. C., Crill W. E. Properties of persistent sodium conductance and calcium conductance of layer V neurons from cat sensorimotor cortex in vitro. J Neurophysiol. 1985 Jan;53(1):153–170. doi: 10.1152/jn.1985.53.1.153. [DOI] [PubMed] [Google Scholar]
  26. Swartz K. J., Bean B. P. Inhibition of calcium channels in rat CA3 pyramidal neurons by a metabotropic glutamate receptor. J Neurosci. 1992 Nov;12(11):4358–4371. doi: 10.1523/JNEUROSCI.12-11-04358.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Westbrook G. L., Mayer M. L. Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons. Nature. 1987 Aug 13;328(6131):640–643. doi: 10.1038/328640a0. [DOI] [PubMed] [Google Scholar]
  28. Xie X. M., Smart T. G. A physiological role for endogenous zinc in rat hippocampal synaptic neurotransmission. Nature. 1991 Feb 7;349(6309):521–524. doi: 10.1038/349521a0. [DOI] [PubMed] [Google Scholar]
  29. Xie X., Smart T. G. Properties of GABA-mediated synaptic potentials induced by zinc in adult rat hippocampal pyramidal neurones. J Physiol. 1993 Jan;460:503–523. doi: 10.1113/jphysiol.1993.sp019484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Zhou F. M., Hablitz J. J. Zinc enhances GABAergic transmission in rat neocortical neurons. J Neurophysiol. 1993 Sep;70(3):1264–1269. doi: 10.1152/jn.1993.70.3.1264. [DOI] [PubMed] [Google Scholar]

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