神經突觸是神經細胞間訊息傳遞的主要通道。而麩胺酸(glutamate)為主要興奮性神經傳導物質，功能除訊息傳導外，也涉及學習與記憶。中樞神經系統中，鋅為腦部含量第二高(僅次於鐵)的微量元素，與麩胺酸共同存在於前突觸端(presynaptic terminal)的synaptic vesicle中，於神經興奮時共同釋放入突觸間隙(synaptic cleft)。之後，鋅離子藉由多種通道進入後突觸端(postsynaptic terminal)。本論文主要在探討細胞內鋅離子對麩胺酸受器的調控。
我們使用二次全細胞電位箝制法，第一次全細胞電位箝制法使用正常的internal solution，第二次全細胞電位箝制法使用內含10μM鋅離子的internal solution。在二次箝制實驗中，我們以藥理學方法，研究細胞內鋅離子對突觸間訊號傳遞(synaptic transmission)之影響，我們也測試細胞對外加麩胺酸受器促效劑的反應，並以Hill equation估計出其最大電流（Imax）、最大電流的二分之一時的打藥時間（EC50）與Hill coefficient。比較前後兩次箝制實驗，得到以下結果：細胞內鋅離子導致spontanous excitatory postsynaptic current （sEPSCs）中穿透過NMDA受器的部分增大2.61±1.23倍，sEPSCs中穿透過non-NNMDA受器的部分增大1.66±0.29倍；並促進神經細胞對外加NMDA與glutamate所引發向內電流之Imax的反應，增大的比值分別為1.73±0.21與4.51±1.18。所以，我們推論細胞內鋅離子可增強麩胺酸受器的活性。

Akers, R.F., Lovinger, D.M., Colley, P.A., Linden, D.J., Routtenberg, A.（1986）Translocation of protein kinase C activity may mediate hippocampal long-term potentiation. Science 231: 587-589
Assaf, S.Y., Chung, S.H.（1984）Release of endogenous Zn2+ from brain tissue during activity. Nature 308: 734-736
Berger, T., Schwarz, C., Kraushaar, U., Monyer, H.（1998）Dentate gyrus basket cell GABAA receptors are blocked by Zn2+ via changes of their desensitization kinetics: an in situ patch-clamp and single-cell PCR study. J. Neurosci. 18: 2437-2448
Bliss, T.V.P., Collingridge, G.L.（1993）A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361: 31-39
Chen, L., Huang, L.Y.M. （1992）Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature 356: 521-523
Chen, N., Moshaver, A., Raymond, L.A.（1997）Differential sensitivity of recombinant N-Methy-D-Asparte receptor subtypes to zinc inhibition. Mol. Phamacol. 51: 1015-1023
Choi, D.W., Yokoyama, M., Koh, J.（1988）Zinc neurotoxicity in cortical cell culture. Neuroscience 24: 67-79
Choi, Y.B., Lipton, S.A.（1999）Identification and mechanism of action of two histidine residues underlying high-affinity Zn2+ inhibition of the NMDA receptor. Neuron 23: 171-180
Christine, C.W., Choi D.W.（1990）Effect of zinc on NMDA receptor-mediated channel currents in cortical neurons. J. Neurosci. 10: 108-116
Cotman, C.W., Iversen, L.L.（1987）Excitatory amino acid in the brain: focus on NMDA receptors. Trends Neurosci. 10: 263-265
Collingridge, G.L., Watkins, J.C.（1994）in The NMDA Receptor（Collingride, G.L., Watkins, J.C., eds）2nd ed., pp 1-103. Oxford University Press.
Crawford, I.L., Conner, J.D.（1973）Localisation and release of glutamic acid in relation to the hippocampal mossy fibre pathway. Nature 244: 442-443
Csermely, P., Szamel, M., Resch, K., Somogy, J.（1988）Zinc can increase the activity of protein kinase C and contributes to its binding to plasma membranes in T lymphocytes. J. Biol. Chem. 263: 6487-6490
Donevan, S.D., Rogawski, M.A.（1993）GYKI 52466, a 2,3- benzodiazepine, is a highly selective, neuroprotective antagonist of AMPA/kainite receptor reponses. Neuron 10: 51-59
Ehlers, M.D., Zhang, S., Bernhadt, J.P., Huganir, R.L.（1996）Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84: 745-55
Forbes, I.J., Zalewski, P.D., Giannakis, C., Betts, W.H.（1990）Zinc induces specific association of PKC with membrane cytoskeleton. Biochem. Int. 22: 741-8
Frederickson, C.J.（1989）Neurobiology of zinc and zinc-containing neurons. Int. Rev. Neurobiol. 31: 145-238
Gaskin, F., Kress, Y., Brosan, C., Bornstem., M. （1978）Abnormal tubulin aggregation induced by zinc sulfate in organotypic cultures of nerve tissue. Neuroscience 3: 1117-1128
Hesketh, J.E. (1982) Zinc-stimulated microtubule assembly and evidence for zinc binding to tubulin. Int. J. Biochem. 14: 983-90
Heinemann, S.（1994）Cloned glutamate receptors. Ann. Rev. Neurosci. 17: 31-108
Howell, G.A., Welch, M.G., Fredericjson, C.J.（1984）Stimulation-induced uptake and release of zinc in hippocampal slices. Nature 308: 736-738
Hu, G.Y., Hvalby, O., Walaas, S.I., Albert, K.A., Skjeflo, P., Andersen, P., Greengard, P.（1987）Protein kinase C injection into hippocampal pyramidal cells elicites features of long tern potentiation. Nature 328: 426-429
Hubbard, S.R., Bishop, W.R., Kirschmeier, P., George, S.J., Cramer, S.P., Hendrickson, W.A.（1991）Identification and characterization of zinc binding sites in protein kinase C. Science 254: 1776-1779
Legendre, P., Westbrook, G.L.（1990）The inhibition of single N-methyl-D-aspartate-activated channels by zinc ions on cultured rat neurons. J. Physiol(Lond). 429: 429-449
Malenka, R.C., Kauer, J.A., Perkel, D.J., Mauk, M.D., Kelly, P.T., Nicoll, R.A., Waxham, M.N.（1989）An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 340: 554-557
Malinow, R., Madison, D.V., Tsien, R.W.（1988）Persistance protein kinase activity underlying long-term potentiation. Nature 335: 820-824
Malinow, R., Schulman, H., Tsien, R.W.（1989）Inhition of postsynaptic PKC or CaMKII blocks induction but expression of LTP. Science 245: 862-866
Mayer, M.L. & Wetbrook, G.L.（1987）The physiology of excitatory amino acids in the vertebrate central nervous system. Prog. Neurobiol. 28: 197-276
Mayer, M.L. & Jr, L.V（1989）The action of zinc on synaptiv transmission and neuronal excitability in cultures of mouse hippocampus. J. Physiol. 415: 351-365
Mills, J.W., Zhou, J.H., Cardoza, L., Ferm, V.H.（1992）Zinc alters actin filaments in Madin-Darby canine kidney cells. : Toxicol. Appl. Pharmacol. 116: 92-100
Monaghan, D.T., Bridge, R.J., Cotman, C.W.（1989）The excitatory amino acid receptors. Am. Rev. Pharmacol. Toxicol. 29: 365- 402
Murakami, K., Whitelet, M.K., Routtenberg, A.（1987）Regulation of protein kinase C activity by cooperative interaction of Zn2+ and Ca2+. J. Biol. Chem.262: 13902-13960
Nakanishi, S.（1994）Metabotropic glutamate receptors: synaptic transmission, modulation and plasticity. Neuron 13: 1031- 1037
Nansheng, C., Ali, M., Lynn, A.R. （1997）Differential sensitivity of recombinant N-methyl-D-aspartate receptor subtypes to zinc inhibition. Mol. Pharmacol. 51: 10115-1023
Patemain, A.V., Morales, M., Lerma, J.（1995）Selective Antagonism of AMPA receptors unmasks kainite receptor-mediated responses in hippocampal neurons. Neuron 14: 185-189
Paoletti, P., Ascher, P., Neyton, J.（1997）High-affinity zinc inhibition of NMDA NR1-NR2A receptors. J. Neurosci. 17: 5711-5725
Peters, S., Koh, J., Choi, D.W.（1987）Zinc selectively blocks the action of N-meyhyl-D-aspartate on cortical neurons. Science 236: 589-593
Pin, J.P., Duvoisin, R.（1995）The metabotropic glutamate receptors: structure and function. Neurophamacol. 34: 1-26
Quest, A.F.G., Bloomenthal, J., Bardes, E.S.G., Bell, R.M.（1992）The regulatory domain of protein kinase C coordinates four atoms of zinc. J. Biol. Chem. 267: 10193-10197
Rober, C.M., Julie, A.K., David, J.P., Michael, D.M., Paul, T.K., Roger, A.N., M. Neal Waxham.（1989）An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 340: 554-557
Roberto, M., Howard, S., Richard, W.T.（1989）Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science 245: 862-866
Rosenmund, C., Westbrook, L.（1993）Calcium-induced actin depolymerization reduced NMDA channel activity. Neuron 10: 805-814
Rossum, D.V., Kuhse, J., Betz, H.（1999）Dynamic interaction between soluble tublin and c-terminal domains of N- methyl-D-aspartate receptor subunits. J. Neurochemis. 72: 962-973
Sahara, Y., Robinson, H.P.C., Miwa, A., Kawai, N.（1991）Avoltage-clamp study of the effects of Juro spinder toxin and zinc on excitatory synaptic transmission in CA1 pyramidal cells of the guinea pig hippocampal slice. Neurosci. Res. 10: 200-210
Sensi, S.L., Canzoniero, L.M.T., Yu, S.P., Ting, H.S., Koh,J.Y,Kerchner, G.A.,Choi, D.W.（1997）Measurement of intracellular free zinc in living cortical neurons：routes of entry. J. Neurosci. 17: 9554-9564
Tabata, T., Ishida, A.T.（1999）A zinc-dependent Cl- current in Neuronal somata. J. Neurosci. 19: 5195-5240
Thomas, B., Cordelia, S., Udo, K., Hannah, M.（1998）Dentate gurus basket cell GABAA receptors are blocked by Zn2+ via changes of their desensitization kinetics：an in situ patch-clamp and single-cell PCR study. J. Neurosci. 18: 2437-2448
Tingley, W.G., Ehlers, M.D., Kameyama, K., Doherty, C., Ptak, J.B., Riley, C.T., Hunganir, R.L.（1997）Characterization of protein kinase A and protein kinase C phosphorylation of the N-Methyl-D-aspartate receptor NR1 subunit using phosphorylation site-specific antibodies. J. Biol. Chem. 272: 5157-5166
Traynelis, S.F., Burgess, M.F., Zheng, F., Lyuboslavsky, P., Powers, J.L.（1998）Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subtype. J. Neurosci. 18: 6163-6175
Vogt, K., Mellor, J., Tong, G., Nicoll, R.（2000）The actions of synaptically release zinc at hippocampal mossy fiber synapses. Neuron 26: 187-196
Westbrook, G.L., Mayer, M.L.（1987）Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons. Nature 328: 640-643
Wallwork, J.C.（1987）Zinc and the central nervous system. Prog. Food nutr. 11: 203-247
Williams, K.（1996）Separating dual effects of zinc at recombinant N-methyl-D-aspartate receptors. Neurosci. Lett. 215: 9-12
Wyszynski, M., Lin, J., Rao, A., Nigh, E., Beggs, A.H., Crail, A.M., Sheng, M.（1997）Competitive binding of α-actinin and calmodulin to the NMDA receptor. Nature 385: 439-442
Xie, X., Gerber, U., Gahwiler, B.H., Smart, T.G.（1993）Interaction of zinc with ionotropic and metabotropic glutamate receptors in rat hippocampal slices. Neurosci. Lett. 159: 46-50
Xie, X., Smart, G.（1994）Modulation of long term potentiation in rat hippocampal pyramidal neurons by zinc. Pfluger Arch 427: 481-486
Zalewski, P.D., Forbes, I.J., Giannakis, C., Cowled, P.A., Betts, W.H.（1990）Synergy between zinc and phorbol ester in translocation of protein kinase C to cytoskeleton. FEBS Lett. 273: 131-4
葉家成（1999）鼠大腦神經元發育早期興奮性突觸生成與樹突小刺消長之關聯性研究研究. 國立清