Connexins pp 323-357 | Cite as

Connexins in the Nervous System

Abstract

This chapter reviews the localizations and physiological roles of connexins in neurons and glia of the central and peripheral nervous systems. Cx32 forms gap junctions in noncompact myelin in Schwann cells, which are thought to form a reflexive communication pathway connecting the outer and inner myelin layers. Cx29 is also expressed in myelinating Schwann cells, but does not appear to form gap junctions; its role remains to be elucidated. Mutations in CX32 cause an X-linked form of the inherited neuropathy Charcot-Marie-Tooth disease; most such mutations are likely to act through loss of function. Connexins may also play an important role in proliferating Schwann cells. Oligodendrocytes express Cx32, Cx47, and Cx29, while astrocytes express Cx43, Cx30, and possibly Cx26. Although astrocytes are extensively coupled to each other in vivo, oligodendrocyte coupling in vivo is demonstrable only to astrocytes, most via heterotypic Cx43–Cx47 or Cx30–Cx32 junctions. These junctions, along with those between astrocytes, may play a role in spatial buffering of K+ ions and neurotransmitters, and may influence severity of tissue damage during ischemia. Mutations in CX47 cause Pelizaeus Merzbacher–like disease while mutations in CX43 cause oculodentodigital dysplasia. Only Cx36 and Cx45 have been definitively identified in nonretinal brain neurons, where they form electrical synapses; neuron–neuron coupling may play a role in the pathogenesis of epilepsy.

Keywords

Glia Oligodendrocyte Astrocyte Schwann cell Neuron X-linked Charcot-Marie-Tooth disease Pelizaeus Merzbacher–like disease Oculodentodigital dysplasia Tremor Epilepsy Ischemia Cx26 Cx29 Cx30 Cx32 Cx43 Cx47 

Notes

Acknowledgments

This work is supported by National Institutes of Health (NIH) grants 1K02NS50345 and 1R01NS050705 to CKA.

References

  1. 1.
    Raine CS, Wisniewski H, Prineas J. An ultrastructural study of experimental demyelination and remyelination. II. Chronic experimental allergic encephalomyelitis in the peripheral nervous system. Lab Invest. 1969;21:316–27.PubMedGoogle Scholar
  2. 2.
    Bergoffen J, Scherer SS, Wang S, Scott MO, Bone LJ, Paul DL, Chen K, Lensch MW, Chance PF, Fischbeck KH. Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 1993;262:2039–42.Google Scholar
  3. 3.
    Li X, Lynn BD, Olson C, Meier C, Davidson KG, Yasumura T, Rash JE, Nagy JI. Connexin29 expression, immunocytochemistry and freeze-fracture replica immunogold labeling (FRIL) in sciatic nerve. Eur J Neurosci. 2002;16:795–806.Google Scholar
  4. 4.
    Altevogt BM, Kleopa KA, Postma FR, Scherer SS, Paul DL. Connexin29 is uniquely distributed within myelinating glial cells of the central and peripheral nervous systems. J Neurosci. 2002;22:6458–70.PubMedGoogle Scholar
  5. 5.
    Söhl G, Eiberger J, Jung YT, Kozak CA, Willecke K. The mouse gap junction gene connexin29 is highly expressed in sciatic nerve and regulated during brain development. Biol Chem. 2001;382:973–8.PubMedGoogle Scholar
  6. 6.
    Jessen KR, Mirsky R. The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci. 2005;6:671–82.PubMedGoogle Scholar
  7. 7.
    Carroll SL, Miller ML, Frohnert PW, Kim SS, Corbett JA. Expression of neuregulins and their putative receptors, ErbB2 and ErbB3, is induced during Wallerian degeneration. J Neurosci. 1997;17:1642–59.PubMedGoogle Scholar
  8. 8.
    Tetzlaff W. Tight junction contact events and temporary gap junctions in the sciatic nerve fibers of the chicken during Wallerian degeneration and subsequent regeneration. J Neurocytol. 1982;11:839–58.PubMedGoogle Scholar
  9. 9.
    Konishi T. Dye coupling between mouse Schwann cells. Brain Res. 1990;508:85–92.PubMedGoogle Scholar
  10. 10.
    Dezawa M, Mutoh T, Dezawa A, Adachi-Usami E. Putative gap junctional communication between axon and regenerating Schwann cells during mammalian peripheral nerve regeneration. Neuroscience 1998;85:663–7.PubMedGoogle Scholar
  11. 11.
    Dezawa M, Nagano T. Contacts between regenerating axons and the Schwann cells of sciatic nerve segments grafted to the optic nerve of adult rats. J Neurocytol. 1993;22:1103–12.PubMedGoogle Scholar
  12. 12.
    Rosenstein JM, Brightman MW. Regeneration and myelination in autonomic ganglia transplanted to intact brain surfaces. J Neurocytol. 1979;8:359–79.PubMedGoogle Scholar
  13. 13.
    Chanson M, Fanjul M, Bosco D, Nelles E, Suter S, Willecke K, Meda P. Enhanced secretion of amylase from exocrine pancreas of connexin32-deficient mice. J Cell Biol. 1998;141:1267–75.PubMedGoogle Scholar
  14. 14.
    Chandross KJ, Spray DC, Cohen RI, Kumar NM, Kremer M, Dermietzel R, Kessler JA. TNF α inhibits Schwann cell proliferation, connexin46 expression, and gap junctional communication. Mol Cell Neurosci. 1996;7:479–500.PubMedGoogle Scholar
  15. 15.
    Chandross KJ, Chanson M, Spray DC, Kessler JA. Transforming growth factor-β 1 and forskolin modulate gap junctional communication and cellular phenotype of cultured Schwann cells. J Neurosci. 1995;15:262–73.PubMedGoogle Scholar
  16. 16.
    Schnapp BJ, Mugnaini E. Membrane architecture of myelinated fibers as seen by freeze-fracture. In: Waxman SG, editor. Physiology and pathobiology of axons. New York: Raven Press; 1978. pp. 82–123.Google Scholar
  17. 17.
    Sandri C, Van Buren JM, Akert K. Membrane morphology of the vertebrate nervous system. A study with freeze-etch technique. Prog Brain Res. 1977;46:1–384.PubMedGoogle Scholar
  18. 18.
    Scherer SS, Deschenes SM, Xu YT, Grinspan JB, Fischbeck KH, Paul DL. Connexin32 is a myelin-related protein in the PNS and CNS. J Neurosci. 1995;15:8281–94.PubMedGoogle Scholar
  19. 19.
    Balice-Gordon RJ, Bone LJ, Scherer SS. Functional gap junctions in the Schwann cell myelin sheath. J Cell Biol. 1998;142:1095–104.PubMedGoogle Scholar
  20. 20.
    Sutor B, Schmolke C, Teubner B, Schirmer C, Willecke K. Myelination defects and neuronal hyperexcitability in the neocortex of connexin 32-deficient mice. Cereb Cortex. 2000;10:684–97.PubMedGoogle Scholar
  21. 21.
    Chandross KJ, Kessler JA, Cohen RI, Simburger E, Spray DC, Bieri P, Dermietzel R. Altered connexin expression after peripheral nerve injury. Mol Cell Neurosci. 1996;7:501–18.PubMedGoogle Scholar
  22. 22.
    Mambetisaeva ET, Gire V, Evans WH. Multiple connexin expression in peripheral nerve, Schwann cells, and Schwannoma cells. J Neurosci Res. 1999;57:166–75.PubMedGoogle Scholar
  23. 23.
    Meier C, Dermietzel R, Davidson KG, Yasumura T, Rash JE. Connexin32-containing gap junctions in Schwann cells at the internodal zone of partial myelin compaction and in Schmidt-Lanterman incisures. J Neurosci. 2004;24:3186–98.PubMedGoogle Scholar
  24. 24.
    Satake M, Yoshimura T, Ohnishi A, Kobayashi T. Connexin32 gene expression in rat sciatic nerves and cultured Schwann cells. Dev Neurosci. 1997;19:189–95.PubMedGoogle Scholar
  25. 25.
    Miller RG, da Silva PP. Particle rosettes in the periaxonal Schwann cell membrane and particle clusters in the axolemma of rat sciatic nerve. Brain Res. 1977;130:135–41.PubMedGoogle Scholar
  26. 26.
    Stolinski C, Breathnach AS, Martin B, Thomas PK, King RH, Gabriel G. Associated particle aggregates in juxtaparanodal axolemma and adaxonal Schwann cell membrane of rat peripheral nerve. J Neurocytol. 1981;10:679–91.PubMedGoogle Scholar
  27. 27.
    Anzini P, Neuberg DH, Schachner M, Nelles E, Willecke K, Zielasek J, Toyka KV, Suter U, Martini R. Structural abnormalities and deficient maintenance of peripheral nerve myelin in mice lacking the gap junction protein connexin 32. J Neurosci. 1997;17:4545–51.PubMedGoogle Scholar
  28. 28.
    Scherer SS, Xu YT, Nelles E, Fischbeck K, Willecke K, Bone LJ. Connexin32-null mice develop demyelinating peripheral neuropathy. Glia. 1998;24:8–20.PubMedGoogle Scholar
  29. 29.
    Oh S, Ri Y, Bennett MVL, Trexler EB, Verselis VK, Bargiello TA. Changes in permeability caused by connexin 32 mutations underlie X-linked Charcot-Marie-Tooth disease. Neuron 1997;19:927–38.PubMedGoogle Scholar
  30. 30.
    Teubner B, Odermatt B, Guldenagel M, Söhl G, Degen J, Bukauskas F, Kronengold J, Verselis VK, Jung YT, Kozak CA, Schilling K, Willecke K. Functional expression of the new gap junction gene connexin47 transcribed in mouse brain and spinal cord neurons. J Neurosci. 2001;21:1117–26.PubMedGoogle Scholar
  31. 31.
    Odermatt B, Wellershaus K, Wallraff A, Seifert G, Degen J, Euwens C, Fuss B, Bussow H, Schilling K, Steinhauser C, Willecke K. Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS. J Neurosci. 2003;23:4549–59.PubMedGoogle Scholar
  32. 32.
    Kleopa KA, Orthmann JL, Enriquez A, Paul DL, Scherer SS. Unique distributions of the gap junction proteins connexin29, connexin32, and connexin47 in oligodendrocytes. Glia. 2004;47:346–57.PubMedGoogle Scholar
  33. 33.
    Uhlenberg B, Schuelke M, Ruschendorf F, Ruf N, Kaindl AM, Henneke M, Thiele H, Stoltenburg-Didinger G, Aksu F, Topaloglu H, Nurnberg P, Hubner C, Weschke B, Gartner J. Mutations in the gene encoding gap junction protein α 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am J Hum Genet. 2004;75:251–60.PubMedGoogle Scholar
  34. 34.
    Toews JC, Schram V, Weerth SH, Mignery GA, Russell JT. Signaling proteins in the axoglial apparatus of sciatic nerve nodes of Ranvier. Glia. 2007;55:202–13.PubMedGoogle Scholar
  35. 35.
    Li J, Habbes HW, Eiberger J, Willecke K, Dermietzel R, Meier C. Analysis of connexin expression during mouse Schwann cell development identifies connexin29 as a novel marker for the transition of neural crest to precursor cells. Glia. 2007;55:93–103.PubMedGoogle Scholar
  36. 36.
    Eiberger J, Kibschull M, Strenzke N, Schober A, Bussow H, Wessig C, Djahed S, Reucher H, Koch DA, Lautermann J, Moser T, Winterhager E, Willecke K. Expression pattern and functional characterization of connexin29 in transgenic mice. Glia. 2006;53:601–11.PubMedGoogle Scholar
  37. 37.
    Tang W, Zhang Y, Chang Q, Ahmad S, Dahlke I, Yi H, Chen P, Paul DL, Lin X. Connexin29 is highly expressed in cochlear Schwann cells, and it is required for the normal development and function of the auditory nerve of mice. J Neurosci. 2006;26:1991–9.PubMedGoogle Scholar
  38. 38.
    Brightman MW, Reese TS. Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol. 1969;40:648–77.PubMedGoogle Scholar
  39. 39.
    Quigley HA. Gap junctions between optic nerve head astrocytes. Invest Ophthalmol Visual Sci. 1977;16:582–5.Google Scholar
  40. 40.
    Dermietzel R. Junctions in the central nervous system of the cat. 3. Gap junctions and membrane-associated orthogonal particle complexes (MOPC) in astrocytic membranes. Cell Tissue Res. 1974;149:121–35.PubMedGoogle Scholar
  41. 41.
    Massa PT, Mugnaini E. Cell junctions and intramembrane particles of astrocytes and oligodendrocytes: a freeze-fracture study. Neuroscience 1982;7:523–38.PubMedGoogle Scholar
  42. 42.
    Rash JE, Staines WA, Yasumura T, Patel D, Furman CS, Stelmack GL, Nagy JI. 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;97:7573–8.PubMedGoogle Scholar
  43. 43.
    Rash JE, Olson CO, Pouliot WA, Davidson KG, Yasumura T, Furman CS, Royer S, Kamasawa N, Nagy JI, Dudek FE. Connexin36 vs. connexin32, ‘miniature’ neuronal gap junctions, and limited electrotonic coupling in rodent suprachiasmatic nucleus. Neuroscience 2007;149:350–371.PubMedGoogle Scholar
  44. 44.
    Altevogt BM, Paul DL. Four classes of intercellular channels between glial cells in the CNS. J Neurosci. 2004;24:4313–23.PubMedGoogle Scholar
  45. 45.
    Nagy JI, Ionescu AV, Lynn BD, Rash JE. Connexin29 and connexin32 at oligodendrocyte and astrocyte gap junctions and in myelin of the mouse central nervous system. J Comp Neurol. 2003;464:356–70.PubMedGoogle Scholar
  46. 46.
    Nagy JI, Li X, Rempel J, Stelmack G, Patel D, Staines WA, Yasumura T, Rash JE. Connexin26 in adult rodent central nervous system: demonstration at astrocytic gap junctions and colocalization with connexin30 and connexin43. J Comp Neurol. 2001;441:302–23.PubMedGoogle Scholar
  47. 47.
    Nagy JI, Ionescu AV, Lynn BD, Rash JE. Coupling of astrocyte connexins Cx26, Cx30, Cx43 to oligodendrocyte Cx29, Cx32, Cx47: implications from normal and connexin32 knockout mice. Glia. 2003;44:205–18.PubMedGoogle Scholar
  48. 48.
    Filippov MA, Hormuzdi SG, Fuchs EC, Monyer H. A reporter allele for investigating connexin 26 gene expression in the mouse brain. Eur J Neurosci. 2003;18:3183–92.PubMedGoogle Scholar
  49. 49.
    Kamasawa N, Sik A, Morita M, Yasumura T, Davidson KG, Nagy JI, Rash JE. Connexin-47 and connexin-32 in gap junctions of oligodendrocyte somata, myelin sheaths, paranodal loops and Schmidt-Lanterman incisures: implications for ionic homeostasis and potassium siphoning. Neuroscience 2005;136:65–86.PubMedGoogle Scholar
  50. 50.
    Menichella DM, Goodenough DA, Sirkowski E, Scherer SS, Paul DL. Connexins are critical for normal myelination in the CNS. J Neurosci. 2003;23:5963–73.PubMedGoogle Scholar
  51. 51.
    Kunzelmann P, Blumcke I, Traub O, Dermietzel R, Willecke K. Coexpression of connexin45 and -32 in oligodendrocytes of rat brain. J Neurocytol. 1997;26:17–22.PubMedGoogle Scholar
  52. 52.
    Pastor A, Kremer M, Moller T, Kettenmann H, Dermietzel R. Dye coupling between spinal cord oligodendrocytes: differences in coupling efficiency between gray and white matter. Glia. 1998;24:108–20.PubMedGoogle Scholar
  53. 53.
    Kruger O, Plum A, Kim JS, Winterhager E, Maxeiner S, Hallas G, Kirchhoff S, Traub O, Lamers WH, Willecke K. Defective vascular development in connexin 45-deficient mice. Development 2000;127:4179–93.PubMedGoogle Scholar
  54. 54.
    Li X, Simard JM. Connexin45 gap junction channels in rat cerebral vascular smooth muscle cells. Am J Physiol Heart Circ Physiol. 2001;281:H1890–8.Google Scholar
  55. 55.
    Li X, Simard JM. Increase in Cx45 gap junction channels in cerebral smooth muscle cells from SHR. Hypertension 2002;40:940–6.PubMedGoogle Scholar
  56. 56.
    Rash JE, Davidson KG, Kamasawa N, Yasumura T, Kamasawa M, Zhang C, Michaels R, Restrepo D, Ottersen OP, Olson CO, Nagy JI. Ultrastructural localization of connexins (Cx36, Cx43, Cx45), glutamate receptors and aquaporin-4 in rodent olfactory mucosa, olfactory nerve and olfactory bulb. J Neurocytol. 2005;34:307–41.PubMedGoogle Scholar
  57. 57.
    Nagy JI, Rash JE. Connexins and gap junctions of astrocytes and oligodendrocytes in the CNS. Brain Res Brain Res Rev. 2000;32:29–44.PubMedGoogle Scholar
  58. 58.
    Nagy JI, Dudek FE, Rash JE. Update on connexins and gap junctions in neurons and glia in the mammalian nervous system. Brain Res Brain Res Rev. 2004;47:191–215.PubMedGoogle Scholar
  59. 59.
    Orthmann-Murphy JL, Freidin M, Fischer E, Scherer SS, Abrams CK. Two distinct heterotypic channels mediate gap junction coupling between astrocyte and oligodendrocyte connexions. J Neurosci. 2007;27:13949–57.Google Scholar
  60. 60.
    Wallraff A, Kohling R, Heinemann U, Theis M, Willecke K, Steinhauser C. The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus. J Neurosci. 2006; 26:5438–47.PubMedGoogle Scholar
  61. 61.
    Theis M, Jauch R, Zhuo L, Speidel D, Wallraff A, Doring B, Frisch C, Söhl G, Teubner B, Euwens C, Huston J, Steinhauser C, Messing A, Heinemann U, Willecke K. Accelerated hippocampal spreading depression and enhanced locomotory activity in mice with astrocyte-directed inactivation of connexin43. J Neurosci. 2003;23:766–76.PubMedGoogle Scholar
  62. 62.
    Wallraff A, Odermatt B, Willecke K, Steinhauser C. Distinct types of astroglial cells in the hippocampus differ in gap junction coupling. Glia. 2004;48:36–43.PubMedGoogle Scholar
  63. 63.
    Rash JE, Yasumura T, Dudek FE, Nagy JI. Cell-specific expression of connexins and evidence of restricted gap junctional coupling between glial cells and between neurons. J Neurosci. 2001;21:1983–2000.PubMedGoogle Scholar
  64. 64.
    Rash JE, Duffy HS, Dudek FE, Bilhartz BL, Whalen LR, Yasumura T. Grid-mapped freeze-fracture analysis of gap junctions in gray and white matter of adult rat central nervous system, with evidence for a ‘panglial syncytium’ that is not coupled to neurons. J Comp Neurol. 1997;388:265–92.PubMedGoogle Scholar
  65. 65.
    Massa PT, Szuchet S, Mugnaini E. Cell-cell interactions of isolated and cultured oligodendrocytes: formation of linear occluding junctions and expression of peculiar intramembrane particles. J Neurosci. 1984;4:3128–39.PubMedGoogle Scholar
  66. 66.
    Kettenmann H, Orkand RK, Schachner M. Coupling among identified cells in mammalian nervous system cultures. J Neurosci. 1983;3:506–16.PubMedGoogle Scholar
  67. 67.
    Kettenmann H, Ransom BR. Electrical coupling between astrocytes and between oligodendrocytes studied in mammalian cell cultures. Glia. 1988;1:64–73.PubMedGoogle Scholar
  68. 68.
    Ransom BR, Kettenmann H. Electrical coupling, without dye coupling, between mammalian astrocytes and oligodendrocytes in cell culture. Glia. 1990;3:258–66.PubMedGoogle Scholar
  69. 69.
    Dermietzel R, Farooq M, Kessler JA, Althaus H, Hertzberg EL, Spray DC. Oligodendrocytes express gap junction proteins connexin32 and connexin45. Glia. 1997;20:101–14.PubMedGoogle Scholar
  70. 70.
    Mugnaini E. Cell junctions of astrocytes, ependyma, and related cells in the mammalian central nervous system, with emphasis on the hypothesis of a generalized functional syncytium of supporting cells. In: Fedoroff S, Vernadakis A, editors. Astrocytes, vol I. New York: Academic Press, 1986. pp. 329–71.Google Scholar
  71. 71.
    Scemes E, Giaume C. Astrocyte calcium waves: what they are and what they do. Glia. 2006; 54:716–25.PubMedGoogle Scholar
  72. 72.
    Neusch C, Rozengurt N, Jacobs RE, Lester HA, Kofuji P. Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination. J Neurosci. 2001;21:5429–38.PubMedGoogle Scholar
  73. 73.
    Higashi K, Fujita A, Inanobe A, Tanemoto M, Doi K, Kubo T, Kurachi Y. An inwardly rectifying K+ channel, Kir4.1, expressed in astrocytes surrounds synapses and blood vessels in brain. Am J Physiol Cell Physiol. 2001;281:C922–31.Google Scholar
  74. 74.
    Li L, Head V, Timpe LC. Identification of an inward rectifier potassium channel gene expressed in mouse cortical astrocytes. Glia. 2001;33:57–71.PubMedGoogle Scholar
  75. 75.
    Menichella DM, Majdan M, Awatramani R, Goodenough DA, Sirkowski E, Scherer SS, Paul DL. Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity. J Neurosci. 2006;26:10984–91.Google Scholar
  76. 76.
    Jiang JX, Gu S. Gap junction- and hemichannel-independent actions of connexins. Biochim Biophys Acta. 2005;1711:208–14.PubMedGoogle Scholar
  77. 77.
    Contreras JE, Sanchez HA, Eugenin EA, Speidel D, Theis M, Willecke K, Bukauskas FF, Bennett MV, Saez JC. Metabolic inhibition induces opening of unapposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in culture. Proc Natl Acad Sci USA. 2002;99:495–500.Google Scholar
  78. 78.
    Dermietzel R, Meier C, Bukauskas F, Spray DC. Following tracks of hemichannels. Cell Commun Adhes. 2003;10:335–40.PubMedGoogle Scholar
  79. 79.
    Sáez JC, Contreras JE, Bukauskas FF, Retamal MA, Bennett MVL. Gap junction hemichannels in astrocytes of the CNS. Acta Physiol Scand. 2003;179:9–22.PubMedGoogle Scholar
  80. 80.
    Retamal MA, Cortes CJ, Reuss L, Bennett MV, Sáez JC. S-nitrosylation and permeation through connexin 43 hemichannels in astrocytes: induction by oxidant stress and reversal by reducing agents. Proc Natl Acad Sci USA. 2006;103:4475–80.Google Scholar
  81. 81.
    Stout CE, Costantin JL, Naus CC, Charles AC. Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J Biol Chem. 2002;277:10482–8.Google Scholar
  82. 82.
    Bennett M, Crain S, Grundfest H. Electrophysiology of supramedullary neuronsin Spheroides maculates: I. Orthodromic and antidromic responses. J Gen Physiol. 1959;43:159–88.PubMedGoogle Scholar
  83. 83.
    Connors BW, Long MA. Electrical synapses in the mammalian brain. Annu Rev Neurosci. 2004;27:393–418.PubMedGoogle Scholar
  84. 84.
    Schmitz D, Schuchmann S, Fisahn A, Draguhn A, Buhl EH, Petrasch-Parwez E, Dermietzel R, Heinemann U, Traub RD. Axo-axonal coupling. A novel mechanism for ultrafast neuronal communication. Neuron 2001;31:831–40.PubMedGoogle Scholar
  85. 85.
    Draguhn A, Traub RD, Schmitz D, Jefferys JG. Electrical coupling underlies high frequency oscillations in the hippocampus in vitro. Nature 1998;394:189–92.PubMedGoogle Scholar
  86. 86.
    Traub RD, Bibbig R, Piechotta A, Draguhn R, Schmitz D. Synaptic and nonsynaptic contributions to giant ipsps and ectopic spikes induced by 4-aminopyridine in the hippocampus in vitro. J Neurophysiol. 2001;85:1246–56.PubMedGoogle Scholar
  87. 87.
    Hamzei-Sichani F, Kamasawa N, Janssen WGM, Yasumura T, Hof PR, Wearne SL, Stewart MG, Young SR, Whittington MA, Rash JE, Traub RD. Evidence for gap junctions on hippocampal mossy fiber axons using thin-section and freeze-fracture replica immunogold labeling electron microscopy. Proc Nat Acad Sci USA. 2007;104:12548–53.Google Scholar
  88. 88.
    O'Brien J, Bruzzone R, White TW, Al-Ubaidi MR, Ripps H. Cloning and expression of two related connexins from the perch retina define a distinct subgroup of the connexin family. J Neurosci. 1998;18:7625–37.PubMedGoogle Scholar
  89. 89.
    Condorelli DF, Parenti R, Spinella F, Trovato Salinaro A, Belluardo N, Cardile V, Cicirata F. Cloning of a new gap junction gene (Cx36) highly expressed in mammalian brain neurons. Eur J Neurosci. 1998;10:1202–8.PubMedGoogle Scholar
  90. 90.
    Söhl G, Degen J, Teubner B, Willecke K. The murine gap junction gene connexin36 is highly expressed in mouse retina and regulated during brain development. FEBS Lett. 1998;428:27–31.PubMedGoogle Scholar
  91. 91.
    Teubner B, Degen J, Söhl G, Guldenagel M, Bukauskas FF, Trexler EB, Verselis VK, De Zeeuw CI, Lee CG, Kozak CA, Petrasch-Parwez E, Dermietzel R, Willecke K. Functional expression of the murine connexin 36 gene coding for a neuron-specific gap junctional protein. J Membr Biol. 2000;176:249–62.PubMedGoogle Scholar
  92. 92.
    Condorelli DF, Trovato-Salinaro A, Mudo G, Mirone MB, Belluardo N. Cellular expression of connexins in the rat brain: neuronal localization, effects of kainate-induced seizures and expression in apoptotic neuronal cells. Eur J Neurosci. 2003;18:1807–27.PubMedGoogle Scholar
  93. 93.
    Maxeiner S, Kruger O, Schilling K, Traub O, Urschel S, Willecke K. Spatiotemporal transcription of connexin45 during brain development results in neuronal expression in adult mice. Neuroscience 2003;119:689–700.PubMedGoogle Scholar
  94. 94.
    Zhang C, Restrepo D. Expression of connexin 45 in the olfactory system. Brain Res. 2002;929:37–47.PubMedGoogle Scholar
  95. 95.
    Guldenagel M, Söhl G, Plum A, Traub O, Teubner B, Weiler R, Willecke K. Expression patterns of connexin genes in mouse retina. J Comp Neurol. 2000;425:193–201.PubMedGoogle Scholar
  96. 96.
    Söhl G, Guldenagel M, Traub O, Willecke K. Connexin expression in the retina. Brain Res Brain Res Rev. 2000;32:138–45.PubMedGoogle Scholar
  97. 97.
    Han Y, Massey SC. Electrical synapses in retinal ON cone bipolar cells: subtype-specific expression of connexins. Proc Natl Acad Sci USA. 2005;102:13313–8.Google Scholar
  98. 98.
    Dedek K, Schultz K, Pieper M, Dirks P, Maxeiner S, Willecke K, Weiler R, Janssen-Bienhold U. Localization of heterotypic gap junctions composed of connexin45 and connexin36 in the rod pathway of the mouse retina. Eur J Neurosci. 2006;24:1675–86.PubMedGoogle Scholar
  99. 99.
    Maxeiner S, Dedek K, Janssen-Bienhold U, Ammermuller J, Brune H, Kirsch T, Pieper M, Degen J, Kruger O, Willecke K, Weiler R. Deletion of connexin45 in mouse retinal neurons disrupts the rod/cone signaling pathway between AII amacrine and ON cone bipolar cells and leads to impaired visual transmission. J Neurosci. 2005; 25:566–76.PubMedGoogle Scholar
  100. 100.
    Chang Q, Gonzalez M, Pinter MJ, Balice-Gordon RJ. Gap junctional coupling and patterns of connexin expression among neonatal rat lumbar spinal motor neurons. J Neurosci. 1999;19:10813–28.PubMedGoogle Scholar
  101. 101.
    Chang Q, Balice-Gordon RJ. Gap junctional communication among developing and injured motor neurons. Brain Res Brain Res Rev. 2000;32:242–9.PubMedGoogle Scholar
  102. 102.
    Eiberger J, Degen J, Romualdi A, Deutsch U, Willecke K, Söhl G. Connexin genes in the mouse and human genome. Cell Commun Adhes. 2001;8:163–5.Google Scholar
  103. 103.
    Hombach S, Janssen-Bienhold U, Söhl G, Schubert T, Bussow H, Ott T, Weiler R, Willecke K. Functional expression of connexin57 in horizontal cells of the mouse retina. Eur J Neurosci. 2004;19:2633–40.PubMedGoogle Scholar
  104. 104.
    O'Brien JJ, Li W, Pan F, Keung J, O'Brien J, Massey SC. Coupling between A-type horizontal cells is mediated by connexin 50 gap junctions in the rabbit retina. J Neurosci. 2006;26:11624–36.Google Scholar
  105. 105.
    Belliveau DJ, Naus CC. Cellular localization of gap junction mRNAs in developing rat brain. Dev Neurosci. 1995;17:81–96.PubMedGoogle Scholar
  106. 106.
    Zhang C, Finger TE, Restrepo D. Mature olfactory receptor neurons express connexin 43. J Comp Neurol. 2000;426:1–12.PubMedGoogle Scholar
  107. 107.
    Priest CA, Thompson AJ, Keller A. Gap junction proteins in inhibitory neurons of the adult barrel neocortex. Somatosens Motor Res. 2001;18:245–52.Google Scholar
  108. 108.
    Nadarajah B, Thomaidou D, Evans WH, Parnavelas JG. Gap junctions in the adult cerebral cortex: regional differences in their distribution and cellular expression of connexins. J Comp Neurol. 1996;376:326–42.PubMedGoogle Scholar
  109. 109.
    Micevych PE, Popper P, Hatton GI. Connexin 32 mRNA levels in the rat supraoptic nucleus: upregulation prior to parturition and during lactation. Neuroendocrinology 1996;63:39–45.PubMedGoogle Scholar
  110. 110.
    Micevych PE, Abelson L. Distribution of mRNAs coding for liver and heart gap junction proteins in the rat central nervous system. J Comp Neurol. 1991;305:96–118.PubMedGoogle Scholar
  111. 111.
    Dermietzel R, Traub O, Hwang TK, Beyer E, Bennett MV, Spray DC, Willecke K. Differential expression of three gap junction proteins in developing and mature brain tissues. Proc Natl Acad Sci USA. 1989;86:10148–52.Google Scholar
  112. 112.
    Alvarez-Maubecin V, Garcia-Hernandez F, Williams JT, Van Bockstaele EJ. Functional coupling between neurons and glia. J Neurosci. 2000;20:4091–8.PubMedGoogle Scholar
  113. 113.
    Froes MM, Correia AH, Garcia-Abreu J, Spray DC, Campos de Carvalho AC, Neto MVL. Gap-junctional coupling between neurons and astrocytes in primary central nervous system cultures. Proc Natl Acad Sci USA. 1999;96:7541–6.Google Scholar
  114. 114.
    Rash JE, Yasumura T, Hudson CS, Agre P, Nielsen S. Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. Proc Natl Acad Sci USA. 1998;95:11981–6.Google Scholar
  115. 115.
    Rash JE, Olson CO, Davidson KGV, Yasumura T, Kamasawa N, Nagy JI. Identification of connexin36 in gap junctions between neurons in rodent locus coeruleus. Neuroscience 2007;147:938–56.PubMedGoogle Scholar
  116. 116.
    Meier C, Dermietzel R. Electrical synapses-gap junctions in the brain. Res Problems Cell Different. 2006;43:99–128.Google Scholar
  117. 117.
    Söhl G, Maxeiner S, Willecke K. Expression and functions of neuronal gap junctions. Nat Rev Neurosci. 2005;6:191–200.PubMedGoogle Scholar
  118. 118.
    Bennett MVL, Zukin RS. Electrical coupling and neuronal synchronization in the mammalian brain. Neuron 2004;41:495–511.PubMedGoogle Scholar
  119. 119.
    Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM. Connexin 26 mutations in hereditary nonsyndromic sensorineural deafness. Nature 1997;387:80–3.PubMedGoogle Scholar
  120. 120.
    Common JE, Becker D, Di WL, Leigh IM, O'Toole EA, Kelsell DP. Functional studies of human skin disease- and deafness-associated connexin 30 mutations. Biochem Biophys Res Commun. 2002;298:651–6.PubMedGoogle Scholar
  121. 121.
    Common JE, O'Toole EA, Leigh IM, Thomas A, Griffiths WA, Venning V, Grabczynska S, Peris Z, Kansky A, Kelsell DP. Clinical and genetic heterogeneity of erythrokeratoderma variabilis. J Invest Dermatol. 2005;125:920–7.PubMedGoogle Scholar
  122. 122.
    Essenfelder GM, Bruzzone R, Lamartine J, Charollais A, Blanchet-Bardon C, Barbe MT, Meda P, Waksman G. Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity. Hum Mol Genet. 2004;13:1703–14.PubMedGoogle Scholar
  123. 123.
    Jan AY, Amin S, Ratajczak P, Richard G, Sybert VP. Genetic heterogeneity of KID syndrome: identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia. J Invest Dermatol. 2004;122:1108–13.PubMedGoogle Scholar
  124. 124.
    Palmada M, Schmalisch K, Bohmer C, Schug N, Pfister M, Lang F, Blin N. Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment. Neurobiol Dis. 2006;22:112–8.PubMedGoogle Scholar
  125. 125.
    Del Castillo I, Moreno-Pelayo MA, Del Castillo FJ, Brownstein Z, Marlin S, Adina Q, Cockburn DJ, Pandya A, Siemering KR, Chamberlin GP, Ballana E, Wuyts W, Maciel-Guerra AT, Alvarez A, Villamar M, Shohat M, Abeliovich D, Dahl HH, Estivill X, Gasparini P, Hutchin T, Nance WE, Sartorato EL, Smith RJ, Van Camp G, Avraham KB, Petit C, Moreno F. Prevalence and evolutionary origins of the del(GJB6-D13S1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study. Am J Hum Genet. 2003;73:1452–8.PubMedGoogle Scholar
  126. 126.
    del Castillo FJ, Rodriguez-Ballesteros M, Alvarez A, Hutchin T, Leonardi E, de Oliveira CA, Azaiez H, Brownstein Z, Avenarius MR, Marlin S, Pandya A, Shahin H, Siemering KR, Weil D, Wuyts W, Aguirre LA, Martin Y, Moreno-Pelayo MA, Villamar M, Avraham KB, Dahl HH, Kanaan M, Nance WE, Petit C, Smith RJ, Van Camp G, Sartorato EL, Murgia A, Moreno F, del Castillo I. A novel deletion involving the connexin-30 gene, del(GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 nonsyndromic hearing impairment. J Med Genet. 2005;42:588–94.PubMedGoogle Scholar
  127. 127.
    Lin G, Glass J, Scherer S, Fischbeck K. A unique mutation in Cx32 associated with severe, early onset CMTX in a heterozygous female. Ann NY Acad Sci. 1999;14:481–4.Google Scholar
  128. 128.
    Felice KJ, Seltzer WK. Severe X-linked Charcot-Marie-Tooth neuropathy due to new mutations G59R(G>C), W44X(G>A) in the connexin 32 gene. Eur Neurol. 2000;44:61–3.PubMedGoogle Scholar
  129. 129.
    Nicholson G, Corbett A. Slowing of central conduction in X-linked Charcot-Marie-Tooth neuropathy shown by brain stem auditory evoked responses. J Neurol Neurosurg Psychiatr. 1996;61:43–6.PubMedGoogle Scholar
  130. 130.
    Nicholson GA, Yeung L, Corbett A. Efficient neurophysiologic selection of X-linked Charcot-Marie-Tooth families: ten novel mutations. Neurology 1998;51:1412–6.PubMedGoogle Scholar
  131. 131.
    Hanemann CO, Bergmann C, Senderek J, Zerres K, Sperfeld AD. Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation. Arch Neurol. 2003;60:605–9.PubMedGoogle Scholar
  132. 132.
    Paulson HL, Garbern JY, Hoban TF, Krajewski KM, Lewis RA, Fischbeck KH, Grossman RI, Lenkinski R, Kamholz JA, Shy ME. Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease. Ann Neurol. 2002;52:429–34.PubMedGoogle Scholar
  133. 133.
    Marques W Jr, Sweeney JG, Wood NW, Wroe SJ, Marques W. Central nervous system involvement in a novel connexin 32 mutation affecting identical twins. J Neurol Neurosurg Psychiatr. 1999;66:803–4.PubMedGoogle Scholar
  134. 134.
    Bahr M, Andres F, Timmerman V, Nelis ME, Van Broeckhoven C, Dichgans J. Central visual, acoustic, and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene. J Neurol Neurosurg Psychiatr. 1999;66:202–6.PubMedGoogle Scholar
  135. 135.
    Takashima H, Nakagawa M, Umehara F, Hirata K, Suehara M, Mayumi H, Yoshishige K, Matsuyama W, Saito M, Jonosono M, Arimura K, Osame M. Gap junction protein β 1 (GJB1) mutations and central nervous system symptoms in X-linked Charcot-Marie-Tooth disease. Acta Neurol Scand. 2003;107:31–7.PubMedGoogle Scholar
  136. 136.
    Nicholson G, Nash J. Intermediate nerve conduction velocities define X-linked Charcot-Marie-Tooth neuropathy families. Neurology 1993;43:2558–64.PubMedGoogle Scholar
  137. 137.
    Tabaraud F, Lagrange E, Sindou P, Vandenberghe A, Levy N, Vallat JM. Demyelinating X-linked Charcot-Marie-Tooth disease: unusual electrophysiological findings. Muscle Nerve. 1999;22:1442–7.PubMedGoogle Scholar
  138. 138.
    Senderek J, Bergmann C, Quasthoff S, Ramaekers VT, Schroder JM. X-linked dominant Charcot-Marie-Tooth disease: nerve biopsies allow morphological evaluation and detection of connexin32 mutations (Arg15Trp, Arg22Gln). Acta Neuropathol. 1998;95:443–9.PubMedGoogle Scholar
  139. 139.
    Senderek J, Hermanns B, Bergmann C, Boroojerdi B, Bajbouj M, Hungs M, Ramaekers VT, Quasthoff S, Karch D, Schroder JM. X-linked dominant Charcot-Marie-Tooth neuropathy: clinical, electrophysiological, and morphological phenotype in four families with different connexin32 mutations. J Neurol Sci. 1999;167:90–101.PubMedGoogle Scholar
  140. 140.
    Hahn AF, Ainsworth PJ, Bolton CF, Bilbao JM, Vallat JM. Pathological findings in the X-linked form of Charcot-Marie-Tooth disease: a morphometric and ultrastructural analysis. Acta Neuropathol. 2001;101:129–39.PubMedGoogle Scholar
  141. 141.
    Ainsworth PJ, Bolton CF, Murphy BC, Stuart JA, Hahn AF. Genotype/phenotype correlation in affected individuals of a family with a deletion of the entire coding sequence of the connexin 32 gene. Hum Genet. 1998;103:242–4.PubMedGoogle Scholar
  142. 142.
    Lin C, Numakura C, Ikegami T, Shizuka M, Shoji M, Nicholson G, Hayasaka K. Deletion and nonsense mutations of the connexin 32 gene associated with Charcot-Marie-Tooth disease. Tohoku J Exp Med. 1999;188:239–44.PubMedGoogle Scholar
  143. 143.
    Nakagawa M, Takashima H, Umehara F, Arimura K, Miyashita F, Takenouchi N, Matsuyama W, Osame M Clinical phenotype in X-linked Charcot-Marie-Tooth disease with an entire deletion of the connexin 32 coding sequence. J Neurol Sci. 2001;185:31–7.PubMedGoogle Scholar
  144. 144.
    Ionasescu VV, Searby C, Ionasescu R, Neuhaus IM, Werner R. Mutations of the noncoding region of the connexin32 gene in X-linked dominant Charcot-Marie-Tooth neuropathy. Neurology 1996;47:541–4.PubMedGoogle Scholar
  145. 145.
    Flagiello L, Cirigliano V, Strazzullo M, Cappa V, Ciccodicola A, D’Esposito M, Torrente I, Werner R, Di Iorio G, Rinaldi M, Dallapiccola A, Forabosco A, Ventruto V, D’Urso M. Mutation in the nerve-specific 5'noncoding region of Cx32 gene and absence of specific mRNA in a CMTX1 Italian family. Hum Mutat. 1998;12:361.PubMedGoogle Scholar
  146. 146.
    Ionasescu V, Ionasescu R, Searby C. Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy. Am J Med Genet. 1996;63:486–91.PubMedGoogle Scholar
  147. 147.
    Shy ME, Siskind C, Swan ER, Krajewski KM, Doherty T, Fuerst DR, Ainsworth PJ, Lewis RA, Scherer SS, Hahn AF. CMT1X phenotypes represent loss of GJB1 gene function. Neurology 2007;68:849–55.PubMedGoogle Scholar
  148. 148.
    Abrams CK, Oh S, Ri Y, Bargiello TA. Mutations in connexin 32: the molecular and biophysical bases for the X-linked form of Charcot-Marie-Tooth disease. Brain Res Brain Res Rev. 2000;32:203–14.PubMedGoogle Scholar
  149. 149.
    Ressot C, Gomes D, Dautigny A, Pham-Dinh D, Bruzzone R. Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties. J Neurosci. 1998;18:4063–75.PubMedGoogle Scholar
  150. 150.
    Wang HL, Chang WT, Yeh TH, Wu T, Chen MS, Wu CY. Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease. Neurobiol Dis. 2004;15:361–70.PubMedGoogle Scholar
  151. 151.
    Bruzzone R, White TW, Scherer SS, Fischbeck KH, Paul DL. Null mutations of connexin32 in patients with X-linked Charcot-Marie-Tooth disease. Neuron 1994;13:1253–60.PubMedGoogle Scholar
  152. 152.
    Omori Y, Mesnil M, Yamasaki H. Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant-negative effects. Mol Biol Cell. 1996;7:907–16.PubMedGoogle Scholar
  153. 153.
    Yoshimura T, Satake M, Ohnishi A, Tsutsumi Y, Fujikura Y. Mutations of connexin32 in Charcot-Marie-Tooth disease type X interfere with cell-to-cell communication but not cell proliferation and myelin- specific gene expression. J Neurosci Res. 1998;51:154–61.PubMedGoogle Scholar
  154. 154.
    Deschenes SM, Walcott JL, Wexler TL, Scherer SS, Fischbeck KH. Altered trafficking of mutant connexin32. J Neurosci. 1997;17:9077–84.PubMedGoogle Scholar
  155. 155.
    Yum SW, Kleopa KA, Shumas S, Scherer SS. Diverse trafficking abnormalities of connexin32 mutants causing CMTX. Neurobiol Dis. 2002;11:43–52.PubMedGoogle Scholar
  156. 156.
    Kleopa KA, Yum SW, Scherer SS. Cellular mechanisms of connexin32 mutations associated with CNS manifestations. J Neurosci Res. 2002;68:522–34.PubMedGoogle Scholar
  157. 157.
    VanSlyke JK, Deschenes SM, Musil LS. Intracellular transport, assembly, and degradation of wildtype and disease-linked mutant gap junction proteins. Mol Biol Cell. 2000;11:1933–46.PubMedGoogle Scholar
  158. 158.
    Jeng LJ, Balice-Gordon RJ, Messing A, Fischbeck KH, Scherer SS. The effects of a dominant connexin32 mutant in myelinating Schwann cells. Mol Cell Neurosci. 2006;32:283–98.PubMedGoogle Scholar
  159. 159.
    Abrams CK, Bennett MVL, Verselis VK, Bargiello TA. Voltage opens unopposed gap junction hemichannels formed by a connexin 32 mutant associated with X-linked Charcot-Marie-Tooth disease. Proc Natl Acad Sci USA. 2002;99:3980–4.Google Scholar
  160. 160.
    Liang GS, de Miguel M, Gomez-Hernandez JM, Glass JD, Scherer SS, Mintz M, Barrio LC, Fischbeck KH. Severe neuropathy with leaky connexin32 hemichannels. Ann Neurol. 2005;57:749–54.PubMedGoogle Scholar
  161. 161.
    Loddenkemper T, Grote K, Evers S, Oelerich M, Stogbauer F. Neurological manifestations of the oculodentodigital dysplasia syndrome. J Neurol. 2002;249:584–95.PubMedGoogle Scholar
  162. 162.
    Ginsberg LE, Jewett T, Grub R, McLean WT. Oculodental digital dysplasia: neuroimaging in a kindred. Neuroradiology 1996;38:84–6.PubMedGoogle Scholar
  163. 163.
    Gutmann DH, Zackai EH, McDonald-McGinn DM, Fischbeck KH, Kamholz J. Oculodentodigital dysplasia syndrome associated with abnormal cerebral white matter. Am J Med Gen. 1991;41:18–20.Google Scholar
  164. 164.
    Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE, Innis JW, Dinulos MB, Christian C, Hannibal MC, Jabs EW. Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet. 2003;72:408–18.PubMedGoogle Scholar
  165. 165.
    Flenniken AM, Osborne LR, Anderson N, Ciliberti N, Fleming C, Gittens JE, Gong XQ, Kelsey LB, Lounsbury C, Moreno L, Nieman BJ, Peterson K, Qu D, Roscoe W, Shao Q, Tong D, Veitch GI, Voronina I, Vukobradovic I, Wood GA, Zhu Y, Zirngibl RA, Aubin JE, Bai D, Bruneau BG, Grynpas M, Henderson JE, Henkelman RM, McKerlie C, Sled JG, Stanford WL, Laird DW, Kidder GM, Adamson SL, Rossant J. A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia. Development 2005;132:4375–86.PubMedGoogle Scholar
  166. 166.
    Lai A, Le DN, Paznekas WA, Gifford WD, Jabs EW, Charles AC. Oculodentodigital dysplasia connexin43 mutations result in non-functional connexin hemichannels and gap junctions in C6 glioma cells. J Cell Sci. 2006;119:532–41.PubMedGoogle Scholar
  167. 167.
    McLachlan E, Manias JL, Gong XQ, Lounsbury CS, Shao Q, Bernier SM, Bai D, Laird DW. Functional characterization of oculodentodigital dysplasia-associated Cx43 mutants. Cell Commun Adhes. 2005;12:279–92.PubMedGoogle Scholar
  168. 168.
    Shibayama J, Paznekas W, Seki A, Taffet S, Jabs EW, Delmar M, Musa H. Functional characterization of connexin43 mutations found in patients with oculodentodigital dysplasia. Circ Res. 2005;96:e83–91.Google Scholar
  169. 169.
    Gong XQ, Shao Q, Lounsbury CS, Bai D, Laird DW. Functional characterization of a GJA1 frameshift mutation causing oculodentodigital dysplasia and palmoplantar keratoderma. J Biol Chem. 2006;281:31801–11.Google Scholar
  170. 170.
    Roscoe W, Veitch GI, Gong XQ, Pellegrino E, Bai D, McLachlan E, Shao Q, Kidder GM, Laird DW. Oculodentodigital dysplasia-causing connexin43 mutants are non-functional and exhibit dominant effects on wildtype connexin43. J Biol Chem. 2005;280:11458–66.Google Scholar
  171. 171.
    Reaume AG, De Sousa PA, Kulkarni S, Langille BL, Zhu D, Davies TC, Juneja SC, Kidder GM, Rossant J. Cardiac malformation in neonatal mice lacking connexin43. Science 1995;267:1831–4.PubMedGoogle Scholar
  172. 172.
    Garbern JY. Pelizaeus-Merzbacher disease: genetic and cellular pathogenesis. Cell Mol Life Sci. 2007;64:50–65.PubMedGoogle Scholar
  173. 173.
    Salviati L, Trevisson E, Baldoin MC, Toldo I, Sartori S, Calderone M, Tenconi R, Laverda A. A novel deletion in the GJA12 gene causes Pelizaeus-Merzbacher-like disease. Neurogenetics 2007;8:57–60.PubMedGoogle Scholar
  174. 174.
    Wolf NI, Cundall M, Rutland P, Rosser E, Surtees R, Benton S, Chong WK, Malcolm S, Ebinger F, Bitner-Glindzicz M, Woodward KJ. Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination. Neurogenetics 2007;8:39–44.PubMedGoogle Scholar
  175. 175.
    Bugiani M, Al Shahwan S, Lamantea E, Bizzi A, Bakhsh E, Moroni I, Balestrini MR, Uziel G, Zeviani M. GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy. Neurology 2006;67:273–9.PubMedGoogle Scholar
  176. 176.
    Orthmann-Murphy JL, Enriquez AD, Abrams CK, Scherer SS. Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease. Mol Cell Neurosci. 2007;34:629–41.PubMedGoogle Scholar
  177. 177.
    Traub RD, Draguhn A, Whittington MA, Baldeweg T, Bibbig A, Buhl EH, Schmitz D. Axonal gap junctions between principal neurons: a novel source of network oscillations, and perhaps epileptogenesis. Rev Neurosci. 2002;13:1–30.PubMedGoogle Scholar
  178. 178.
    Rouach N, Avignone E, Meme W, Koulakoff A, Venance L, Blomstrand F, Giaume C. Gap junctions and connexin expression in the normal and pathological central nervous system. Biol Cell. 2002;94:457–75.PubMedGoogle Scholar
  179. 179.
    Nemani VM, Binder DK. Emerging role of gap junctions in epilepsy. Histol Histopathol. 2005;20:253–9.PubMedGoogle Scholar
  180. 180.
    Maier N, Guldenagel M, Söhl G, Siegmund H, Willecke K, Draguhn A. Reduction of high frequency network oscillations (ripples) and pathological network discharges in hippocampal slices from connexin 36-deficient mice. J Physiol. 2002;541:521–8.PubMedGoogle Scholar
  181. 181.
    De Zeeuw CI, Chorev E, Devor A, Manor Y, Van Der Giessen RS, De Jeu MT, Hoogenraad CC, Bijman J, Ruigrok TJ, French P, Jaarsma D, Kistler WM, Meier C, Petrasch-Parwez E, Dermietzel R, Söhl G, Gueldenagel M, Willecke K, Yarom Y. Deformation of network connectivity in the inferior olive of connexin 36-deficient mice is compensated by morphological and electrophysiological changes at the single neuron level. J Neurosci. 2003;23:4700–11.PubMedGoogle Scholar
  182. 182.
    Song J, Tanouye MA. Seizure suppression by shakB2, a gap junction mutation in Drosophila. J Neurophysiol. 2006;95:627–35.PubMedGoogle Scholar
  183. 183.
    Yang L, Ling DS. Carbenoxolone modifies spontaneous inhibitory and excitatory synaptic transmission in rat somatosensory cortex. Neurosci Lett. 2007;416:221–6.PubMedGoogle Scholar
  184. 184.
    Gigout S, Louvel J, Pumain R. Effects in vitro and in vivo of a gap junction blocker on epileptiform activities in a genetic model of absence epilepsy. Epilepsy Res. 2006;69:15–29.PubMedGoogle Scholar
  185. 185.
    Samoilova M, Li J, Pelletier MR, Wentlandt K, Adamchik Y, Naus CC, Carlen PL. Epileptiform activity in hippocampal slice cultures exposed chronically to bicuculline: increased gap junctional function and expression. J Neurochem. 2003;86:687–99.PubMedGoogle Scholar
  186. 186.
    Ross FM, Gwyn P, Spanswick D, Davies SN. Carbenoxolone depresses spontaneous epileptiform activity in the CA1 region of rat hippocampal slices. Neuroscience 2000;100:789–96.PubMedGoogle Scholar
  187. 187.
    Bostanci MO, Bagirici F. Anticonvulsive effects of carbenoxolone on penicillin-induced epileptiform activity: an in vivo study. Neuropharmacology 2007;52:362–7.PubMedGoogle Scholar
  188. 188.
    Bostanci MO, Bagirici F. The effects of octanol on penicillin induced epileptiform activity in rats: an in vivo study. Epilepsy Res. 2006;71:188–94.PubMedGoogle Scholar
  189. 189.
    Gajda Z, Szupera Z, Blazso G, Szente M. Quinine, a blocker of neuronal Cx36 channels, suppresses seizure activity in rat neocortex in vivo. Epilepsia 2005;46:1581–91.PubMedGoogle Scholar
  190. 190.
    Szente M, Gajda Z, Said Ali K, Hermesz E. Involvement of electrical coupling in the in vivo ictal epileptiform activity induced by 4-aminopyridine in the neocortex. Neuroscience 2002;115:1067–78.PubMedGoogle Scholar
  191. 191.
    Proulx E, Leshchenko Y, Kokarovtseva L, Khokhotva V, El-Beheiry M, Snead OC, 3rd, Perez Velazquez JL. Functional contribution of specific brain areas to absence seizures: role of thalamic gap-junctional coupling. Eur J Neurosci. 2006;23:489–96.PubMedGoogle Scholar
  192. 192.
    Srinivas M, Hopperstad MG, Spray DC. Quinine blocks specific gap junction channel subtypes. Proc Natl Acad Sci USA. 2001;98:10942–7.Google Scholar
  193. 193.
    Bikson M, Id Bihi R, Vreugdenhil M, Kohling R, Fox JE, Jefferys JG. Quinine suppresses extracellular potassium transients and ictal epileptiform activity without decreasing neuronal excitability in vitro. Neuroscience 2002;115:251–61.PubMedGoogle Scholar
  194. 194.
    Deuschl G, Raethjen J, Lindemann M, Krack P. The pathophysiology of tremor. Muscle Nerve. 2001;24:716–35.PubMedGoogle Scholar
  195. 195.
    Llinas R, Volkind RA. The olivo-cerebellar system: functional properties as revealed by harmaline-induced tremor. Exp Brain Res. 1973;18:69–87.PubMedGoogle Scholar
  196. 196.
    de Montigny C, Lamarre Y. Rhythmic activity induced by harmaline in the olivo-cerebello-bulbar system of the cat. Brain Res. 1973;53:81–95.PubMedGoogle Scholar
  197. 197.
    Llinas R, Baker R, Sotelo C. Electrotonic coupling between neurons in cat inferior olive. J Neurophysiol. 1974;37:560–71.PubMedGoogle Scholar
  198. 198.
    Llinas R, Yarom Y. Oscillatory properties of guinea-pig inferior olivary neurones and their pharmacological modulation: an in vitro study. J Physiol. 1986;376:163–82.PubMedGoogle Scholar
  199. 199.
    Miwa H, Kubo T, Suzuki A, Kihira T, Kondo T. A species-specific difference in the effects of harmaline on the rodent olivocerebellar system. Brain Res. 2006;1068:94–101.PubMedGoogle Scholar
  200. 200.
    Louis ED, Vonsattel JP, Honig LS, Lawton A, Moskowitz C, Ford B, Frucht S. Essential tremor associated with pathologic changes in the cerebellum. Arch Neurol. 2006;63:1189–93.PubMedGoogle Scholar
  201. 201.
    Louis ED, Vonsattel JP, Honig LS, Ross GW, Lyons KE, Pahwa R. Neuropathologic findings in essential tremor. Neurology 2006;66:1756–9.PubMedGoogle Scholar
  202. 202.
    Long MA, Deans MR, Paul DL, Connors BW. Rhythmicity without synchrony in the electrically uncoupled inferior olive. J Neurosci. 2002;22:10898–905.Google Scholar
  203. 203.
    Placantonakis DG, Bukovsky AA, Zeng XH, Kiem HP, Welsh JP. Fundamental role of inferior olive connexin 36 in muscle coherence during tremor. Proc Natl Acad Sci USA. 2004;101:7164–9.Google Scholar
  204. 204.
    Martin FC, Handforth A. Carbenoxolone and mefloquine suppress tremor in the harmaline mouse model of essential tremor. Mov Disord. 2006;21:1641–9.PubMedGoogle Scholar
  205. 205.
    Perez Velazquez JL, Frantseva MV, Naus CC. Gap junctions and neuronal injury: protectants or executioners? Neuroscientist 2003;9:5–9.PubMedGoogle Scholar
  206. 206.
    Farahani R, Pina-Benabou MH, Kyrozis A, Siddiq A, Barradas PC, Chiu FC, Cavalcante LA, Lai JC, Stanton PK, Rozental R. Alterations in metabolism and gap junction expression may determine the role of astrocytes as ‘good samaritans’ or executioners. Glia. 2005;50:351–61.PubMedGoogle Scholar
  207. 207.
    Lin JH, Yang J, Liu S, Takano T, Wang X, Gao Q, Willecke K, Nedergaard M. Connexin mediates gap junction-independent resistance to cellular injury. J Neurosci. 2003;23:430–41.PubMedGoogle Scholar
  208. 208.
    Nedergaard M, Astrup J. Infarct rim: effect of hyperglycemia on direct current potential and 14C-2-deoxyglucose phosphorylation. J Cereb Blood Flow Metab. 1986;6:607–15.PubMedGoogle Scholar
  209. 209.
    Nakase T, Söhl G, Theis M, Willecke K, Naus CC. Increased apoptosis and inflammation after focal brain ischemia in mice lacking connexin43 in astrocytes. Am J Pathol. 2004;164:2067–75.PubMedGoogle Scholar
  210. 210.
    Rawanduzy A, Hansen A, Hansen TW, Nedergaard M. Effective reduction of infarct volume by gap junction blockade in a rodent model of stroke. J Neurosurg. 1997;87:916–20.PubMedGoogle Scholar
  211. 211.
    John SA, Kondo R, Wang SY, Goldhaber JI, Weiss JN. Connexin-43 hemichannels opened by metabolic inhibition. J Biol Chem. 1999;274:236–40.PubMedGoogle Scholar
  212. 212.
    Thompson RJ, Zhou N, MacVicar BA. Ischemia opens neuronal gap junction hemichannels. Science 2006;312:924–7.PubMedGoogle Scholar
  213. 213.
    Ye ZC, Wyeth MS, Baltan-Tekkok S, Ransom BR. Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J Neurosci. 2003;23:3588–96.PubMedGoogle Scholar
  214. 214.
    Perez Velazquez JL, Kokarovtseva L, Sarbaziha R, Jeyapalan Z, Leshchenko Y. Role of gap junctional coupling in astrocytic networks in the determination of global ischaemia-induced oxidative stress and hippocampal damage. Eur J Neurosci. 2006; 23:1–10.PubMedGoogle Scholar
  215. 215.
    Nakase T, Fushiki S, Naus CC. Astrocytic gap junctions composed of connexin 43 reduce apoptotic neuronal damage in cerebral ischemia. Stroke 2003;34:1987–93.PubMedGoogle Scholar
  216. 216.
    Siushansian R, Bechberger JF, Cechetto DF, Hachinski VC, Naus CC. Connexin43 null mutation increases infarct size after stroke. J Comp Neurol. 2001;440:387–94.PubMedGoogle Scholar
  217. 217.
    Oguro K, Jover T, Tanaka H, Lin Y, Kojima T, Oguro N, Grooms SY, Bennett MV, Zukin RS. Global ischemia-induced increases in the gap junctional proteins connexin 32 (Cx32) and Cx36 in hippocampus and enhanced vulnerability of Cx32 knock-out mice. J Neurosci. 2001;21:7534–42.PubMedGoogle Scholar
  218. 218.
    Rami A, Volkmann T, Winckler J. Effective reduction of neuronal death by inhibiting gap junctional intercellular communication in a rodent model of global transient cerebral ischemia. Exp Neurol. 2001;170:297–304.PubMedGoogle Scholar
  219. 219.
    Warner DS, Ludwig PS, Pearlstein R, Brinkhous AD. Halothane reduces focal ischemic injury in the rat when brain temperature is controlled. Anesthesiology 1995;82:1237–45.PubMedGoogle Scholar
  220. 220.
    Frantseva MV, Kokarovtseva L, Perez Velazquez JL. Ischemia-induced brain damage depends on specific gap-junctional coupling. J Cereb Blood Flow Metab. 2002;22:453–62.PubMedGoogle Scholar
  221. 221.
    Blanc EM, Bruce-Keller AJ, Mattson MP. Astrocytic gap junctional communication decreases neuronal vulnerability to oxidative stress-induced disruption of Ca2+ homeostasis and cell death. J Neurochem. 1998;70:958–70.PubMedGoogle Scholar
  222. 222.
    Lin JH, Weigel H, Cotrina ML, Liu S, Bueno E, Hansen AJ, Hansen TW, Goldman S, Nedergaard M. Gap-junction-mediated propagation and amplification of cell injury. Nat Neurosci. 1998;1:494–500.PubMedGoogle Scholar
  223. 223.
    Barrio LC, Suchyna T, Bargiello T, Xu LX, Roginski RS, Bennett MV, Nicholson BJ. Gap junctions formed by connexins 26 and 32 alone and in combination are differently affected by applied voltage. Proc Natl Acad Sci USA. 1991;88:8410–4.Google Scholar
  224. 224.
    Dahl E, Manthey D, Chen Y, Schwarz HJ, Chang YS, Lalley PA, Nicholson BJ, Willecke K. Molecular cloning and functional expression of mouse connexin-30, a gap junction gene highly expressed in adult brain and skin. J Biol Chem. 1996;271:17903–10.Google Scholar
  225. 225.
    White TW, Paul DL, Goodenough DA, Bruzzone R. Functional analysis of selective interactions among rodent connexins. Mol Biol Cell. 1995;6:459–70.PubMedGoogle Scholar
  226. 226.
    Bukauskas FF, Elfgang C, Willecke K, Weingart R. Heterotypic gap junction channels (connexin26-connexin32) violate the paradigm of unitary conductance. Pflügers Arch. 1995;429:870–2.PubMedGoogle Scholar
  227. 227.
    Werner R, Levine E, Rabadan-Diehl C, Dahl G. Formation of hybrid cell-cell channels. Proc Natl Acad Sci USA. 1989;86:5380–4.Google Scholar
  228. 228.
    Bruzzone R, White TW, Paul DL. Expression of chimeric connexins reveals new properties of the formation and gating behavior of gap junction channels. J Cell Sci. 1994;107:955–67.PubMedGoogle Scholar
  229. 229.
    Nagy JI, Patel D, Ochalski PA, Stelmack GL. Connexin30 in rodent, cat and human brain: selective expression in gray matter astrocytes, colocalization with connexin43 at gap junctions and late developmental appearance. Neuroscience 1999;88:447–68.PubMedGoogle Scholar
  230. 230.
    Li X, Ionescu AV, Lynn BD, Lu S, Kamasawa N, Morita M, Davidson KG, Yasumura T, Rash JE, Nagy JI. Connexin47, connexin29 and connexin32 coexpression in oligodendrocytes and Cx47 association with zonula occludens-1 (ZO-1) in mouse brain. Neuroscience 2004;126:611–30.Google Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Departments of Neurology & Pharmacology and PhysiologyState University of New York Downstate Medical CenterBrooklynUS

Personalised recommendations