Gap Junctions, Fast Oscillations and the Initiation of Seizures

  • Roger D. Traub
  • Hillary Michelson-Law
  • Andrea E. J. Bibbig
  • Eberhard H. Buhl
  • Miles A. Whittington
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 548)


In this chapter, we shall review evidence that gap junctions can contribute to epileptogenesis in the hippocampus and cortex—but not just any gap junctions. Rather, we shall argue for a role for a newly described sort of gap junction, located between the proximal axons of principal neurons. Such axon-axon gap junctions promote epileptogenesis not so much by enhancing synchrony, as by providing pathways for the direct spread of action potentials between neurons. A by-product of such spread is the ability of axonally-coupled neurons to generate oscillations at very high frequencies (>~70 Hz). It is of note that seizure activity, both in vivo and in vitro, has been observed to begin with very high-frequency oscillations. If such oscillations can be shown to initiate the seizure discharge, and not just be an epiphenomenon, then targeting gap junction conductances may prove useful as an anticonvulsant strategy.


Principal Cell Fast Oscillation Gamma Oscillation Juvenile Myoclonic Epilepsy Synaptic Inhibition 


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  1. 1.
    Haas HL, Jefferys JGR. Low-calcium field burst discharges of CAl pyramidal neurones in rat hippocampal slices. J Physiol 1984; 354: 185–201.PubMedGoogle Scholar
  2. 2.
    Taylor CP, Dudek FE. Synchronous neural after discharges in rat hippocampal slices without active chemical synapses. Science 1982; 218: 810–812.PubMedCrossRefGoogle Scholar
  3. 3.
    Taylor CP, Dudek FE. Excitation of hippocampal pyramidal cells by an electrical field effect. J Neurophysiol 1984; 52: 126–142.PubMedGoogle Scholar
  4. 4.
    Schweitzer JS, Patrylo PR, Dudek FE. Prolonged field bursts in the dentate gyrus: Dependence on low calcium, high potassium, and nonsynaptic mechanisms. J Neurophysiol 1992; 68: 2016–2025.PubMedGoogle Scholar
  5. 5.
    Konnerth A, Heinemann U, Yaari Y. Slow transmission of neural activity in hippocampal area CAl in absence of active chemical synapses. Nature 1984; 307: 69–71.PubMedCrossRefGoogle Scholar
  6. 6.
    Traub RD, Dudek FE, Taylor CP et al. Simulation of hippocampal afterdischarges synchronized by electrical interactions. Neuroscience 1985; 14: 1033–1038.PubMedCrossRefGoogle Scholar
  7. 7.
    Jefferys JGR. Influence of electric fields on the excitability of granule cells in guinea-pig hippocampal slices. J Physiol 1981; 319: 143–152.PubMedGoogle Scholar
  8. 8.
    Perez-Velazquez JL, Valiante TA, Carlen PL. Modulation of gap junctional mechanisms during calcium-free induced field burst activity: a possible role for electrotonic coupling in epileptogenesis. J Neurosci 1994; 14: 4308–4317.PubMedGoogle Scholar
  9. 9.
    Schweitzer JS, Wang H, Xiong ZQ et al. pH sensitivity of nonsynaptic field bursts in the dentate gyrus. J Neurophysiol 2000; 84: 927–933.PubMedGoogle Scholar
  10. 10.
    Spray DC, Harris AL, Bennett MVL. Gap junctional conductance is a simple and sensitive function of intracellular pH. Science 1981; 211: 712–715.PubMedCrossRefGoogle Scholar
  11. 11.
    Schmitz D, Schuchmann S, Fisahn A et al. Axo-axonal coupling: a novel mechanism for ultrafast neuronal communication. Neuron 2001; 31: 831–840.PubMedCrossRefGoogle Scholar
  12. 12.
    Buzs£ki G, Horvath Z, Urioste R et al. High-frequency network oscillation in the hippocampus. Science 1992; 256: 025–1027.CrossRefGoogle Scholar
  13. 13.
    Ylinen A, Bragin A, N£dasdy Z et al. Sharp wave-associated high frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms. J Neurosci 1995; 15: 30–46.PubMedGoogle Scholar
  14. 14.
    Grenier F, Timofeev I, Steriade M. Focal synchronization of ripples (80–200 Hz) in neocortex and their neuronal correlates. J Neurophysiol 2001; 86: 1884–1898.PubMedGoogle Scholar
  15. 15.
    Steriade M, Contreras D, Currb Dossi R et al. The slow (1 Hz) oscillation in reticular thalamic and thalamocortical neurons: scenario of sleep rhythm generation in interacting thalamic and neocortical networks. J Neurosci 1993; 13: 3284–3299.PubMedGoogle Scholar
  16. 16.
    Draguhn A, Traub RD, Schmitz D et al. Electrical coupling underlies high-frequency oscillations in the hippocampus in vitro. Nature 1998; 394: 189–192.PubMedCrossRefGoogle Scholar
  17. 17.
    Draguhn A, Traub RD, Bibbig A et al. Ripple (approximately 200-Hz) oscillations in temporal structures. J Clin Neurophysiol 2000; 17: 361–376.PubMedCrossRefGoogle Scholar
  18. 18.
    Spencer WA, Kandel ER. Electrophysiology of hippocampal neurons. IV. Fast prepotentials. J Neurophysiol 1961; 24: 272–285.Google Scholar
  19. 19.
    Schwartzkroin PA, Prince DA. Penicillin-induced epileptiform activity in the hippocampal in vitro preparation. Ann Neurol 1977; 1: 463–469.PubMedCrossRefGoogle Scholar
  20. 20.
    Church J, Baimbridge KG. Exposure to high-pH medium increases the incidence and extent of dye coupling between rat hippocampal CA1 pyramidal neurons in vitro. J Neurosci 1991; 11: 3289–3295.PubMedGoogle Scholar
  21. 21.
    Traub RD, Schmitz D, Jefferys JGR et al. High-frequency population oscillations are predicted to occur in hippocampal pyramidal neuronal networks interconnected by axoaxonal gap junctions. Neuroscience 1999; 92: 407–426.PubMedCrossRefGoogle Scholar
  22. 22.
    Deuchars J, Thomson AM. CAl pyramid-pyramid connections in rat hippocampus in vitro: dual intracellular recordings with biocytin filling. Neuroscience 1996; 74: 1009–1018.PubMedGoogle Scholar
  23. 23.
    Miles R. Synaptic excitation of inhibitory cells by single CA3 hippocampal pyramidal cells of the guinea-pig in vitro. J Physiol 1990; 428: 61–77.PubMedGoogle Scholar
  24. 24.
    Geiger JRP, Lübke J, Roth A et al. Submillisecond AMPA receptor-mediated signaling at a principal neuron-interneuron synapse. Neuron 1997; 18: 1009–1023.PubMedCrossRefGoogle Scholar
  25. 25.
    Traub RD, Bibbig A. A model of high-frequency ripples in the hippocampus, based on synaptic coupling plus axon-axon gap junctions between pyramidal neurons. J Neurosci 2000; 20: 2086–2093.PubMedGoogle Scholar
  26. 26.
    Whittington MA, Stanford IM, Coiling SB et al. Spatiotemporal patterns of 7 frequency oscillations tetanically induced in the rat hippocampal slice. J Physiol 1997; 502: 591–607.PubMedCrossRefGoogle Scholar
  27. 27.
    Traub RD, Whittington MA, Buhl EH et al. A possible role for gap junctions in generation of very fast EEG oscillations preceding the onset of, and perhaps initiating, seizures. Epilepsia 2001; 42: 153–170.PubMedGoogle Scholar
  28. 28.
    Bragin A, Penttonen M, Buzs4ki G. Termination of epileptic afterdischarge in the hippocampus. J Neurosci 1997; 17: 2567–2579.PubMedGoogle Scholar
  29. 29.
    Wong RKS, Traub RD. Synchronized burst discharge in disinhibited hippocampal slice. I. Initiation in CA2–CA3 region. J Neurophysiol 1983; 49: 442–458.PubMedGoogle Scholar
  30. 30.
    Traub RD, Jefferys JGR, Whittington MA. Enhanced NMDA conductances can account for epileptiform activities induced by low Mg2+ in the rat hippocampal slice. J Physiol 1994; 478: 379–393.PubMedGoogle Scholar
  31. 31.
    Perreault P, Avoli M. Physiology and pharmacology of epileptiform activity induced by 4-aminopyridine in rat hippocampal slices. J Neurophysiol 1991; 65: 771–785.PubMedGoogle Scholar
  32. 32.
    Traub RD, Coiling SB, Jefferys JGR. Cellular mechanisms of 4-aminopyridine-induced synchronized after-discharges in the rat hippocampal slice. J Physiol 1995; 489: 127–140.PubMedGoogle Scholar
  33. 33.
    Aram JA, Michelson HB, Wong RKS. Synchronized GABAergic IPSPs recorded in the neocortex after blockade of synaptic transmission mediated by excitatory amino acids. J Neurophysiol 1991; 65: 1034–1041.PubMedGoogle Scholar
  34. 34.
    Michelson HB, Wong RKS. Excitatory synaptic responses mediated by GABAA receptors in the hippocampus. Science 1991; 253: 1420–1423.PubMedCrossRefGoogle Scholar
  35. 35.
    Michelson HB, Wong RKS. Synchronization of inhibitory neurones in the guinea pig hippocampus in vitro. J Physiol 1994; 477: 35–45.PubMedGoogle Scholar
  36. 36.
    Müller W, Misgeld U. Picrotoxin-and 4-aminopyridine-induced activity in hilar neurons in the guinea pig hippocampal slice. J Neurophysiol 1991; 65: 141–147.PubMedGoogle Scholar
  37. 37.
    Avoli M, Methot M, Kawasaki H. GABA-dependent generation of ectopic action potentials in the rat hippocampus. Eur J Neurosci 1998; 10: 2714–2722.PubMedCrossRefGoogle Scholar
  38. 38.
    Traub RD, Bibbig A, Piechotta A et al. Synaptic and nonsynaptic contributions to giant IPSPs and ectopic spikes induced by 4-aminopyridine in the hippocampus in vitro. J Neurophysiol 2001; 85: 1246–1256.PubMedGoogle Scholar
  39. 39.
    Yang Q, Michelson HB. Gap junctions synchronize the firing of inhibitory interneurons in guinea pig hippocampus. Brain Res 2001; 907: 139–143.PubMedCrossRefGoogle Scholar
  40. 40.
    Galarreta M, Hestrin S. A network of fast-spiking cells in the neocortex connected by electrical synapses. Nature 1999; 402: 72–75.PubMedCrossRefGoogle Scholar
  41. 41.
    Gibson JR, Beierlein M, Connors BW. Two networks of electrically coupled inhibitory neurons in neocortex. Nature 1999; 402: 75–79.PubMedCrossRefGoogle Scholar
  42. 42.
    Venance L, Rozov A, Blatow M et al. Connexin expression in electrically coupled postnatal rat brain neurons. Proc Natl Acad Sci USA 2000; 97: 10260–10265.PubMedCrossRefGoogle Scholar
  43. 43.
    Tamis G, Buhl EH, Lörincz A et al. Proximally targeted GABAergic synapses and gap junctions precisely synchronize cortical interneurons. Nat Neurosci 2000; 3: 366–371.CrossRefGoogle Scholar
  44. 44.
    Fukuda T, Kosaka T. Gap junctions linking the dendritic network of GABAergic interneurons in the hippocampus. J Neurosci 2000; 20: 1519–1528.PubMedGoogle Scholar
  45. 45.
    Kosaka T. Gap junctions between nonpyramidal cell dendrites in the rat hippocampus (CA1 and CA3 regions). Brain Res 1983; 271: 157–161.PubMedCrossRefGoogle Scholar
  46. 46.
    Traub RD. Model of synchronized population bursts in electrically coupled interneurons containing active dendritic conductances. J Comput Neurosci 1995; 2: 283–289.PubMedCrossRefGoogle Scholar
  47. 47.
    Stasheff SF, Hines M, Wilson WA. Axon terminal hyperexcitability associated with epileptogenesis in vitro. I. Origin of ectopic spikes. J Neurophysiol 1993; 70: 960–975.Google Scholar
  48. 48.
    Stasheff SF, Mott DD, Wilson WA. Axon terminal hyperexcitability associated with epileptogenesis in vitro. II. Pharmacological regulation by NMDA and GABAA receptors. J Neurophysiol 1993; 70: 976–984.PubMedGoogle Scholar
  49. 49.
    Jang IS, Jeong HJ, Akaike N. Contribution of the Na-K-CI cotransporter on GABAA receptor-mediated presynaptic depolarization in excitatory nerve terminals. J Neurosci 2001; 21: 5962–5972.PubMedGoogle Scholar
  50. 50.
    Thalmann RH, Peck EJ, Ayala GF. Biphasic response of hippocampal pyramidal neurons to GABA. Neurosci Lett 1981; 21: 319–324.PubMedCrossRefGoogle Scholar
  51. 51.
    Wong RKS, Watkins DJ. Cellular factors influencing GABA response in hippocampal pyramidal cells. J Neurophysiol 1982; 48: 938–951.PubMedGoogle Scholar
  52. 52.
    Taira T, Lamsa K, Kaila K. Posttetanic excitation mediated by GABAA receptors in rat CAl pyramidal neurons. J Neurophysiol 1997; 77: 2213–2218.PubMedGoogle Scholar
  53. 53.
    Roelfsema PR, König P, Engel AK et al. Reduced synchronization in the visual cortex of cats with strabismic amblyopia. Eur J Neurosci 1994; 6: 1645–1655.PubMedCrossRefGoogle Scholar
  54. 54.
    Singer W, Gray CM. Visual feature integration and the temporal correlation hypothesis. Ann Rev Neurosci 1995; 18: 555–586.PubMedCrossRefGoogle Scholar
  55. 55.
    Tallon-Baudry C, Bertrand O, Fischer C. Oscillatory synchrony between human extrastriate areas during visual short-term memory maintenance. J Neurosci 2001; 21:RC177:1–5.Google Scholar
  56. 56.
    Fisahn A, Pike FG, Buhl EH et al. Cholinergie induction of network oscillations at 40 Hz in the hippocampus in vitro. Nature 1998; 394: 86–189.CrossRefGoogle Scholar
  57. 57.
    Hormuzdi SG, Pais I, LeBeau FEN. Impaired electrical signaling disrupts gamma frequency oscillations in connexin 36-deficient mice. Neuron 2001; 31: 487–495.PubMedCrossRefGoogle Scholar
  58. 58.
    Towers SK, LeBeau FEN, Gloveli T et al. Fast network oscillations in the rat dentate gyrus in vitro. J Neurophysiol 2002; 87: 1165–1168.PubMedGoogle Scholar
  59. 59.
    LeBeau FEN, Towers SK, Traub RD et al. Fast network oscillations induced by potassium transients in the rat hippocampus in vitro. J Physiol 2002; 542: 167–179.PubMedCrossRefGoogle Scholar
  60. 60.
    Traub RD, Bibbig A, Fisahn A et al. A model of gamma-frequency network oscillations induced in the rat CA3 region by carbachol in vitro. Eur J Neurosci 2000; 12: 4093–4106.PubMedCrossRefGoogle Scholar
  61. 61.
    Traub RD, Jefferys JGR, Whittington MA. Fast Oscillations in Cortical Circuits. Cambridge, MA: MIT Press, 1999.Google Scholar
  62. 62.
    Jones MS, Barth DS. Spatiotemporal organization of fast (200 Hz) electrical oscillations in rat vibrissa/barrel cortex. J Neurophysiol 1999; 82: 1599–1609.PubMedGoogle Scholar
  63. 63.
    Jones MS, MacDonald KD, Choi B et al. Intracellular correlates of fast (200 Hz) electrical oscillations in rat somatosensory cortex. J Neurophysiol 2000; 84: 1505–1518.PubMedGoogle Scholar
  64. 64.
    Bartos M, Vida I, Frotscher M et al. Rapid signaling at inhibitory synapses in a dentate gyrus interneuron network. J Neurosci 2001; 21: 2687–2698.PubMedGoogle Scholar
  65. 65.
    Whittington MA, Traub RD, Jefferys JGR. Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation. Nature 1995; 373: 612–615.PubMedCrossRefGoogle Scholar
  66. 66.
    Traub RD, Whittington MA, Coiling SB et al. Analysis of gamma rhythms in the rat hippocampus in vitro and in vivo. J Physiol 1996; 493: 471–484.PubMedGoogle Scholar
  67. 67.
    Faulkner HJ, Traub RD, Whittington MA. Disruption of synchronous gamma oscillations in the rat hippocampal slice: a common mechanism of anaesthetic drug action. Br J Pharmacol 1998; 125: 483–492.PubMedCrossRefGoogle Scholar
  68. 68.
    Wang X-J, Buzsâki G. Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model. J Neurosci 1996; 16: 6402–6413.PubMedGoogle Scholar
  69. 69.
    White JA, Chow CC, Ritt J et al. Synchronization and oscillatory dynamics in heterogeneous, mutually inhibited neurons. J Comput Neurosci 1998; 5: 5–16.PubMedCrossRefGoogle Scholar
  70. 70.
    Traub RD, Kopell N, Bibbig A et al. Gap junctions between interneuron dendrites can enhance long-range synchrony of gamma oscillations. J Neurosci 2001; 21: 9478–9486.PubMedGoogle Scholar
  71. 71.
    Teubner B, Degen J, Sohl G et al. Functional expression of the murine connexin 36 gene coding for a neuron-specific gap junctional protein. J Membr Biol 2000; 176: 249–262.PubMedCrossRefGoogle Scholar
  72. 72.
    Rash JE, Staines WA, Yasumura T et al. Immunogold evidence that neuronal gap junctions in adult rat brain and spinal cord contain connexin-36 but not connexin-32 or connexin-43. Proc Natl Acad Sci USA 2000; 97: 7573–7578.PubMedCrossRefGoogle Scholar
  73. 73.
    Condorelli DF, Belluardo N, Trovato-Salinaro A et al. Expression of Cx36 in mammalian neurons. Brain Res Brain Res Rev 2000; 32: 72–85.PubMedCrossRefGoogle Scholar
  74. 74.
    Pais I, Hormuzdi SG, Monyer H et al. Sharp wave-like activity in the hippocampus in vitro in mice lacking the gap junction protein connexin 36. J Neurophysiol 2003; 89: 2046–2054.PubMedCrossRefGoogle Scholar
  75. 75.
    Lauri SE, Delany C, Clarke VR et al. Synaptic activation of a presynaptic kainate receptor facilitates AMPA receptor-mediated synaptic transmission at hippocampal mossy fibre synapses. Neuropharm. 2001; 41: 907–915.CrossRefGoogle Scholar
  76. 76.
    Traub RD, Draguhn A, Whittington MA et al. Axonal gap junctions between principal neurons: a novel source of network oscillations, and perhaps epileptogenesis. Rev Neurosci 2002; 13: 1–30.PubMedCrossRefGoogle Scholar
  77. 77.
    Moortgat KT, Bullock TH, Sejnowski TJ. Gap junction effects on precision and frequency of a model pacemaker network. J Neurophysiol 2000; 83: 984–97.PubMedGoogle Scholar
  78. 78.
    Moortgat KT, Bullock TH, Sejnowski TJ. Precision of the pacemaker nucleus in a weakly electric fish: network versus cellular influences. J Neurophysiol 2000; 83: 971–83.PubMedGoogle Scholar
  79. 79.
    Schmitz D, Frerking M, Nicoll RA. Synaptic activation of presynaptic kainate receptors on hippocampal mossy fiber synapses. Neuron 2000; 27: 327–338.PubMedCrossRefGoogle Scholar
  80. 80.
    Schmitz D, Mellor J, Frerking M et al. Presynaptic kainate receptors at hippocampal mossy fiber synapses. Proc Natl Acad Sci USA 2001; 98: 11003–11008.PubMedCrossRefGoogle Scholar
  81. 81.
    Semyanov A, Kullmann DM. Kainate receptor-dependent axonal depolarization and action potential initiation in interneurons. Nat Neurosci 2001; 4: 718–723.PubMedCrossRefGoogle Scholar
  82. 82.
    Ross FM, Gwyn P, Spanswick D et al. Carbenoxolone depresses spontaneous epileptiform activity in the CA1 region of rat hippocampal slices. Neuroscience 2000; 100: 789–796.PubMedCrossRefGoogle Scholar
  83. 83.
    Köhling R, Gladwell SJ, Bracci E et al. Prolonged epileptiform bursting induced by 0-Mg2+ in rat hippocampal slices depends on gap junctional coupling. Neuroscience 2001; 105: 579–587.PubMedCrossRefGoogle Scholar
  84. 84.
    Bragin A, Engel Jr J, Wilson CL et al. Hippocampal and entorhinal cortex high-frequency oscillations (100–500 Hz) in human epileptic brain and in kainic acid-treated rats with chronic seizures. Epilepsia 1999; 40: 127–137.PubMedCrossRefGoogle Scholar
  85. 85.
    Bragin A, Mody I, Wilson CL et al. A local generation of fast ripples in epileptic brain. J Neurosci 2002; 22: 2012–2021.PubMedGoogle Scholar
  86. 86.
    Alarcon G, Binnie CD, Elwes RDC et al. Power spectrum and intracranial EEG patterns at seizure onset in partial epilepsy. Electroencephalogr Clin Neurophysiol 1995; 94: 326–337.PubMedCrossRefGoogle Scholar
  87. 87.
    Fisher RS, Webber WRS, Lesser RP et al. High-frequency EEG activity at the start of seizures. J Clin Neurophysiol 1992; 9: 441–448.PubMedCrossRefGoogle Scholar
  88. 88.
    Belluardo N, Trovato-Salinaro A, Mudo G et al. Structure, chromosomal localization, and brain expression of human Cx36 gene. J Neurosci Res 1999; 57: 740–752.PubMedCrossRefGoogle Scholar
  89. 89.
    Neubauer BA, Fiedler B, Himmelein B et al. Centrotemporal spikes in families with rolandic epilepsy: linkage to chromosome 15814. Neurology 1998; 51: 1608–1612.PubMedCrossRefGoogle Scholar
  90. 90.
    Sander T, Schulz H, Vieira-Saeker AM et al. Evaluation of a putative major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15814. Am J Med Genet 1999; 88: 182–187.PubMedCrossRefGoogle Scholar
  91. 91.
    Bragin A, Engel Jr J, Wilson CL et al. High-frequency oscillations in the human brain. Hippocampus 1999; 9: 137–142.PubMedCrossRefGoogle Scholar
  92. 92.
    Nagy GS. Evaluation of carbenoxolone sodium in the treatment of duodenal ulcer. Gastroenterology 1978; 74: 7–10.PubMedGoogle Scholar
  93. 93.
    Jellinck PH, Monder C, McEwen BS et al. Differential inhibition of 11 beta-hydroxysteroid dehydrogenase by carbenoxolone in rat brain regions and peripheral tissues. J Steroid Biochem Molec Biol 1993; 46: 209–213.PubMedCrossRefGoogle Scholar
  94. 94.
    Dobbins KR, Saul RF. Transient visual loss after licorice ingestion. J Neuroophthalmol 2000; 20: 38–41.PubMedCrossRefGoogle Scholar
  95. 95.
    Guldenagel M, Ammermuller J, Feigenspan A et al. Visual transmission deficits in mice with targeted disruption of the gap junction gene connexin36. J Neurosci 2001; 21: 6036–6044.PubMedGoogle Scholar
  96. 96.
    Buckmaster PS, Dudek FE. In vivo intracellular analysis of granule cell axon reorganization in epileptic rats. J Neurophysiol 1999; 81: 712–721.PubMedGoogle Scholar
  97. 97.
    Chang Q, Pereda A, Pinter MJ et al. Nerve injury induces gap junctional coupling among axotomized adult motor neurons. J Neurosci 2000; 20: 674–684.PubMedGoogle Scholar
  98. 98.
    Traub RD, Pais I, Bibbig A et al. Contrasting roles of axonal (pyramidal cell) and dendritic (inter-neuron) electrical coupling in the generation of neuronal network oscillations. Proc Natl Acad Sci USA 2003; 100: 1370–1374.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Roger D. Traub
  • Hillary Michelson-Law
  • Andrea E. J. Bibbig
  • Eberhard H. Buhl
  • Miles A. Whittington

There are no affiliations available

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