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Redox modulation of synaptic responses and plasticity in rat CA1 hippocampal neurons

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Abstract

Effects of redox reagents on excitatory and inhibitory synaptic responses as well as on the bidirectional plasticity of α-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA) andN-methyl-d-aspartate (NMDA) receptor-mediated synaptic responses were studied in CA1 pyramidal neurons in rat hippocampal slices. The oxidizing agent 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB, 200 μM) did not affect AMPA, GABAA or GABAB receptor-mediated synaptic responses or the activation of presynaptic metabotropic receptors. However, DTNB irreversibly decreased (by approximately 50%) currents evoked by focal application of NMDA. DTNB also decreased the NMDA component of the EPSC. The reversal potential of NMDA currents and the Mg2+ block were not modified. In the presence of physiological concentrations of Mg2+ (1.3 mM), DTNB did not affect the NMDA receptor-dependent induction of long-term potentiation (LTP) or long-term depression (LTD) expressed by AMPA receptors. In contrast, DTNB fully prevented LTP and LTD induced and expressed by NMDA receptors. Plasticity of NMDA receptor-mediated synaptic responses could be reinstated by the reducing agenttris-(2-carboxyethyl) phosphine (TCEP, 200 μM). These results suggest that persistent, bidirectional changes in synaptic currents mediated by NMDA receptors cannot be evoked when these receptors are in an oxidized state, whereas NMDA-dependent LTP and LTD are still expressed by AMPA receptors. Our observations raise the possibility of developing therapeutic agents that would prevent persistent excitotoxic enhancement of NMDA receptor-mediated events without blocking long-term modifications of AMPA receptor-mediated synaptic responses, thought to underlie memory processes.

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References

  • Abe K, Kimura H (1996) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16:1066–1071

    PubMed  CAS  Google Scholar 

  • Aizenman E, Lipton S, Loring R (1989) Selective modulation of NMDA responses by reduction and oxidation. Neuron 2:1257–1263

    Article  PubMed  CAS  Google Scholar 

  • Andiné P, Jacobson I, Hagberg H (1988) Calcium uptake evoked by electrical stimulation is enhanced postischemically and precedes delayed neuronal death in CA1 area of rat hippocampus, involvement of NMDA receptors. J Cereb Blood Flow Metab 8:799–807

    PubMed  Google Scholar 

  • Aniksztejn L, Ben-Ari Y (1995) The expression of LTP by AMPA and/or NMDA receptors is determined by the extent of NMDA receptors activation during the tetanus. J Neurophysiol 74: 2349–2357

    PubMed  CAS  Google Scholar 

  • Andrade R (1991) Blockade of neurotransmitter-activated K+ conductance by QX-314 in the rat hippocampus. Eur J Pharmacol 199:259–262

    Article  PubMed  CAS  Google Scholar 

  • Ashwood T, Wheal H (1987) The expression ofN-methyl-d-aspartate receptor-mediated component during epileptiform synaptic activity in the hippocampus. Br J Pharmacol 91:815–822

    PubMed  CAS  Google Scholar 

  • Avoli M, Olivier A (1987) Bursting in human epileptogenic neocortex is depressed by anN-methyl-d-aspartate antagonist. Neurosci Lett 76:249–254

    Article  PubMed  CAS  Google Scholar 

  • Asztely F, Wigstrom H, Gustaffson B (1992) The relative contribution of NMDA receptor channels in the expression of long-term potentiation in the hippocampal CA1 region. Eur J Neurosci 4:681–690

    Article  PubMed  Google Scholar 

  • Barrantes E (1980) Modulation of acetylcholine receptor states by thiol modification. Biochemistry 19:2957–2965

    Article  PubMed  CAS  Google Scholar 

  • Baskys A, Malenka RC (1991) Agonists at metabotropic glutamate metabotropic receptors presynaptically inhibit EPSC8 in neonatal rat hippocampus. J Physiol (Lond) 444:687–701

    CAS  Google Scholar 

  • Bashir Z, Alford S, Davies S, Randall A, Collingridge G (1991) Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus. Nature 349:367–380

    Article  Google Scholar 

  • Bear M, Malenka R (1994) Synaptic plasticity, LTP and LTD. Curr Opin Neurobiol 4:389–399

    Article  PubMed  CAS  Google Scholar 

  • Ben-Ari Y, Represa A (1990) Brief seizure episode induces long-term potentiation and mossy fiber sprouting in the hippocampus. Trends Neurosci 13:312–318

    Article  PubMed  CAS  Google Scholar 

  • Ben-Ari Y, Aniksztejn L, Bregestovski P (1992) Protein kinase C modulation of NMDA currents, an important link for LTP induction. Trends Neurosci 15:333–339

    Article  PubMed  CAS  Google Scholar 

  • Bernard C, Hirsch J, Ben-Ari Y (1995) Non-involvement of the redox site of NMDA receptors in bidirectional synaptic plasticty in the CA1 area of the rat hippocampus in vitro. Neurosci Lett 193:197–200

    Article  PubMed  CAS  Google Scholar 

  • Bernard C, Wheal H (1995a) Simultaneous expression of long-term depression of NMDA receptor-mediated synaptic transmission and long-term potentiation of AMPA responses in the hippocampus. Eur J Neurosci 7:1651–1655

    Article  PubMed  CAS  Google Scholar 

  • Bernard C, Wheal H (1995b) Expression of EPSP/spike potentiation following low frequency and tetanic stimulation in the CA1 area of the rat hippocampus. J Neurosci 15:6542–6551

    PubMed  CAS  Google Scholar 

  • Berretta N, Berton F, Bianchi R, Brunelli M, Capogna M, Francesconi W (1991) Long-term potentiation of NMDA receptor-mediated EPSP in guinea-pig hippocampal slices. Eur J Neurosci 3:850–854

    Article  PubMed  Google Scholar 

  • Collingridge G, Kehl S, McLennan H (1983) Excitatory amino acids transmission in the Schaffer collateral-commissural pathway of rat hippocampus. J Physiol (Lond) 334:33–46

    CAS  Google Scholar 

  • Crunelli V, Forda S, Kelly J (1983) Blockade of amino-acid-induced depolarizations and inhibition of excitatory post-synaptic potentials in rat dentate gyrus. J Physiol (Lond) 341:627–640

    CAS  Google Scholar 

  • Dohlman H, Thorner J, Caron M, Lefkowitz R (1991) Model of systems for the study of seven-transmembrane-segment receptors. Annu Rev Biochem 60:653–688

    Article  PubMed  CAS  Google Scholar 

  • Furuhashi M, Ando M, Bielinska M, Pixley M, Shikone T, Hsueh A, Boime I (1994) Mutagenesis of cysteine residues in the human gonadotropin alpha subunit. Roles of individual disulfide bonds in secretion, assembly, and biological activity. J Biol Chem 269:25543–25548

    PubMed  CAS  Google Scholar 

  • Gozlan H, Diabira D, Chinestra P, Ben-Ari Y (1994) Anoxic LTP is mediated by the redox modulatory site of the NMDA receptor. J Neurophysiol 72:3017–3022

    PubMed  CAS  Google Scholar 

  • Gozlan H, Khazipov R, Ben-Ari Y (1995a) Multiple forms of long-term potentiations and multiple regulatory sites ofN-methyl-d-aspartate receptors: role of the redox site. J Neurobiol 26:360–369

    Article  PubMed  CAS  Google Scholar 

  • Gozlan H, Khazipov R, Diabira R, Ben-Ari Y (1995b) In CA1 hippocampal neurons, the redox state of NMDA receptors determines LTP expressed by NMDA but not AMPA receptors. J Neurophysiol 73:2612–2617

    PubMed  CAS  Google Scholar 

  • Gozlan H, Ben-Ari Y (1995) NMDA receptor redox sites: are they targets for selective neuronal protection? Trends Pharmacol Sci 16:368–374

    Article  PubMed  CAS  Google Scholar 

  • Hammond C, Crépel V, Gozlan H, Ben-Ari Y (1994) Anoxic LTP sheds light on the multiple facets of NMDA receptors. Trends Neurosci 17:497–503

    Article  PubMed  CAS  Google Scholar 

  • Köhr G, Eckardt S, Luddens H, Monyer H, Seeburg P (1994) NMDA receptors channels: subunit-specific potentiation by reducing agents. Neuron 12:1031–1040

    Article  PubMed  Google Scholar 

  • Kombian S, Malenka R (1994) Simultaneous LTP of non-NMDA-and LTD of NMDA-receptor-mediated responses in the nucleus accumbens. Nature 368:242–246

    Article  PubMed  CAS  Google Scholar 

  • Levy D, Sucher N, Lipton S (1990) Redox modulation of NMDA receptor-mediated toxicity in mammalian central neurons. Neurosci Lett 110:291–296

    Article  PubMed  CAS  Google Scholar 

  • Li H, Hsu P, Sachais B, Krause J, Leeman S, Boyd N (1996) Identification of the site in the substance P (NK-1) receptor for modulation of peptide binding in sulfhydryl reagents. J Biol Chem 271:1950–1956

    Article  PubMed  CAS  Google Scholar 

  • Lipton S, Rosenberg P (1994) Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330: 613–622

    Article  PubMed  CAS  Google Scholar 

  • Luhman H, Mudrick-Donnon L, Mittmann T, Heinemann U (1995) Ischaemic-induced long-term hyperexcitability in rat neocortex. Eur J Neurosci 7:180–191

    Article  Google Scholar 

  • McNamara J (1994) Cellular and molecular basis of epilepsy. J Neurosci 14:3413–3425

    PubMed  CAS  Google Scholar 

  • McBain C, Mayer M (1994)N-methyl-d-aspartic acid receptor structure and function. Physiol Rev 74:723–760

    PubMed  CAS  Google Scholar 

  • Mody I, Stanton P, Heinemann U (1988) Activation ofN-methyl-d-aspartate receptors parallels changes in cellular and synaptic properties of dentate gyrus granule cells after kindling. J Neurophysiol 59:1033–1054

    PubMed  CAS  Google Scholar 

  • Nowak L, Bregetovski P, Ascher P, Herbet A, Prochiantz A (1984) Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307:462–465

    Article  PubMed  CAS  Google Scholar 

  • Otani S, Ben-Ari Y (1993) Biochemical correlates of long-term potentiation in hippocampal synapses. Int Rev Neurobiol 35: 1–41

    Article  PubMed  CAS  Google Scholar 

  • Pan Z, Bahring R, Grantyn R, Lipton S (1995) Differential modulation by sulhydryl redox agents and glutathione of GABA-and glycine-evoked currents in rat retinal ganglion cells. J Neurosci 15:1384–1391

    PubMed  CAS  Google Scholar 

  • Quesada O, Hirsch J, Ben-Ari Y, Bernard C (1996) Redox site of NMDA receptors can modulate epileptiform activity in hippocampal slices from kainic acid-treated rats. Neurosci Lett 212: 171–174

    Article  PubMed  CAS  Google Scholar 

  • Reynolds I, Rush E, Aizenman E (1990) Reduction of NMDA receptors with dithiothreitol increases MK-801 binding and NMDA-induced Calcium in fluxes. Eur J Pharmacol 101: 178–182

    CAS  Google Scholar 

  • Ruiz-Gomez A, Fernandez-Shaw C, Morato E, Marvizon J, Vasquez J, Valdivieso F, Mayor E (1991) Sulfhydril groups modulate the allosteric interaction between glycine binding sites at the inhibitory glycine receptor. J Neurochem 56:1690–1697

    PubMed  CAS  Google Scholar 

  • Schmid G, Bonanno G, Raiteri M (1996) Functional evidence for two native GABAA receptor subtypes in adult rat hippocampus and cerebellum. Neuroscience 73:697–704

    Article  PubMed  CAS  Google Scholar 

  • Selig D, Hjelmstad G, Herron C, Nicoll R, Malenka R (1996) In-dependent mechanisms for long-term depression of AMPA and NMDA responses. Neuron 15:417–426

    Article  Google Scholar 

  • Spruston N, Jonas P, Sakmann B (1995) Dendritic glutamate receptor channels in rat hippocampal CA3 and CA1 pyramidal neurons. J Physiol (Lond) 482:325–352

    CAS  Google Scholar 

  • Sullivan J, Traynelis S, Chen V, Escobar W, Heinemann S, Lipton A (1994) Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor. Neuron 13:929–936

    Article  PubMed  CAS  Google Scholar 

  • Tang L, Aizenman E (1993) The modulation ofN-methyl-d-aspartate receptors by redox and alkylating reagents in rat cortical neurones in vitro. J Physiol (Lond) 465:303–323

    CAS  Google Scholar 

  • Tauck DL (1992) Redox modulation of NMDA receptor-mediated synaptic activity in the hippocampus. Neuroreport 3:781–784

    PubMed  CAS  Google Scholar 

  • Tauck D, Ashbeck A (1990) Glycine synergistically potentiates the enhancement of LTP induced by a sulfhydryl reducing agent. Brain Res 519:129–132

    Article  PubMed  CAS  Google Scholar 

  • Xiao M, Karpefors M, Niu Y, Wigstrom H (1995) The complementary nature of long-term depression and potentiation revealed by dual component excitatory postsynaptic potentials in hippocampal slices from young rats. Neuroscience 68:625–635

    Article  PubMed  CAS  Google Scholar 

  • Xiao M, Wigstrom H, Gustafsson B (1994) Long-term depression in the hippocampal CA1 region is associated with equal changes in AMPA and NMDA receptor-mediated synaptic responses. Eur J Neurosci 6:1055–1057

    Article  PubMed  CAS  Google Scholar 

  • Xie X, Berger T, Barrionuevo G (1992) Isolated NMDA receptor-mediated synaptic responses express both LTP and LTD. J Neurophysiol 67:1009–1013

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. INSERM U29, Hôpital de Port-Royal, 123 Bld de Port-Royal, F-75634, Paris Cedex 14, France

    C. Bernard, J. C. Hirsch, R. Khazipov, Y. Ben-Ari & H. Gozlan

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  1. C. Bernard
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  2. J. C. Hirsch
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  3. R. Khazipov
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  4. Y. Ben-Ari
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  5. H. Gozlan
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Bernard, C., Hirsch, J.C., Khazipov, R. et al. Redox modulation of synaptic responses and plasticity in rat CA1 hippocampal neurons. Exp Brain Res 113, 343–352 (1997). https://doi.org/10.1007/BF02450332

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  • DOI: https://doi.org/10.1007/BF02450332

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