Gap junctions and hemichannels composed of connexins: Potential therapeutic targets for neurodegenerative diseases

Frontiers in Cellular Neuroscience

Volumn 8, Issue SEP, 2014, Pages

  Takeuchi, Hideyuki ^a   Suzumura, Akio ^a  

^a NAGOYA UNIVERSITY   (Japan)

Author keywords

Connexin; Gap junction; Glutamate; Hemichannel; Microglia; Neurodegeneration; Neuroinflammation

Indexed keywords

EID: 84906912090     PISSN: 16625102     EISSN: None     Source Type: Journal    
DOI: 10.3389/fncel.2014.00189     Document Type: Review

References (202)

1. Aarum, J., Sandberg, K., Haeberlein, S. L., and Persson, M. A. (2003). Migration and differentiation of neural precursor cells can be directed by microglia. Proc. Natl. Acad. Sci. U.S.A. 100, 15983-15988. doi: 10.1073/pnas.2237050100
2. Akiyama, H., and McGeer, P. L. (1990). Brain microglia constitutively express beta-2 integrins. J. Neuroimmunol. 30, 81-93. doi: 10.1016/0165-5728(90)90055-R
3. Allen, K., Fuchs, E. C., Jaschonek, H., Bannerman, D. M., and Monyer, H. (2011). Gap junctions between interneurons are required for normal spatial coding in the hippocampus and short-term spatial memory. J. Neurosci. 31, 6542-6552. doi: 10.1523/JNEUROSCI.6512-10.2011
4. Al-Ubaidi, M. R., White, T. W., Ripps, H., Poras, I., Avner, P., Gomes, D., et al. (2000). Functional properties, developmental regulation, and chromosomal localization of murine connexin36, a gap-junctional protein expressed preferentially in retina and brain. J. Neurosci. Res. 59, 813-826. doi: 10.1002/(SICI)1097-4547(20000315)59:6<813::AID-JNR14>3.0.CO;2-#
5. Altevogt, B. M., Kleopa, K. A., Postma, F. R., Scherer, S. S., and Paul, D. L. (2002). Connexin29 is uniquely distributed within myelinating glial cells of the central and peripheral nervous systems. J. Neurosci. 22, 6458-6470.
6. Altevogt, B. M., and Paul, D. L. (2004). Four classes of intercellular channels between glial cells in the CNS. J. Neurosci. 24, 4313-4323. doi: 10.1523/JNEUROSCI.3303-03.2004
7. Alvarez-Maubecin, V., Garcia-Hernandez, F., Williams, J. T., and Van Bockstaele, E. J. (2000). Functional coupling between neurons and glia. J. Neurosci. 20, 4091-4098.
8. Anderson, C. M., and Swanson, R. A. (2000). Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32, 1-14. doi: 10.1002/1098-1136(200010)32:1<1::AID-GLIA10>3.0.CO;2-W
9. Anzini, P., Neuberg, D. H., Schachner, M., Nelles, E., Willecke, K., Zielasek, J., et al. (1997). Structural abnormalities and deficient maintenance of peripheral nerve myelin in mice lacking the gap junction protein connexin 32. J. Neurosci. 17, 4545-4551.
10. Bamberger, M. E., Harris, M. E., McDonald, D. R., Husemann, J., and Landreth, G. E. (2003). A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J. Neurosci. 23, 2665-2674.
11. Bani-Yaghoub, M., Bechberger, J. F., Underhill, T. M., and Naus, C. C. (1999a). The effects of gap junction blockage on neuronal differentiation of human NTera2/clone D1 cells. Exp. Neurol. 156, 16-32. doi: 10.1006/exnr.1998.6950
12. Bani-Yaghoub, M., Underhill, T. M., and Naus, C. C. (1999b). Gap junction blockage interferes with neuronal and astroglial differentiation of mouse P19 embryonal carcinoma cells. Dev. Genet. 24, 69-81. doi: 10.1002/(SICI)1520-6408(1999)24:1/2<69::AID-DVG8>3.0.CO;2-M
13. Barbe, M. T., Monyer, H., and Bruzzone, R. (2006). Cell-cell communication beyond connexins: the pannexin channels. Physiology (Bethesda) 21, 103-114. doi: 10.1152/physiol.00048.2005
14. Barger, S. W., and Basile, A. S. (2001). Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function. J. Neurochem. 76, 846-854. doi: 10.1046/j.1471-4159.2001.00075.x
15. Bessis, A., Bechade, C., Bernard, D., and Roumier, A. (2007). Microglial control of neuronal death and synaptic properties. Glia 55, 233-238. doi: 10.1002/glia.20459
16. Bittman, K. S., and Loturco, J. J. (1999). Differential regulation of connexin 26 and 43 in murine neocortical precursors. Cereb. Cortex 9, 188-195. doi: 10.1093/cercor/9.2.188
17. Block, M. L., Zecca, L., and Hong, J. S. (2007). Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57-69. doi: 10.1038/nrn2038
18. Boche, D., Perry, V. H., and Nicoll, J. A. (2013). Review: activation patterns of microglia and their identification in the human brain. Neuropathol. Appl. Neurobiol. 39, 3-18. doi: 10.1111/nan.12011
19. Boillee, S., Yamanaka, K., Lobsiger, C. S., Copeland, N. G., Jenkins, N. A., Kassiotis, G., et al. (2006). Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389-1392. doi: 10.1126/science.1123511
20. Bouskila, Y., and Dudek, F. E. (1993). Neuronal synchronization without calciumdependent synaptic transmission in the hypothalamus. Proc. Natl. Acad. Sci. U.S.A. 90, 3207-3210. doi: 10.1073/pnas.90.8.3207
21. Brand-Schieber, E., Werner, P., Iacobas, D. A., Iacobas, S., Beelitz, M., Lowery, S. L., et al. (2005). Connexin43, the major gap junction protein of astrocytes, is downregulated in inflamed white matter in an animal model of multiple sclerosis. J. Neurosci. Res. 80, 798-808. doi: 10.1002/jnr.20474
22. Bruijn, L. I., Miller, T. M., and Cleveland, D. W. (2004). Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu. Rev. Neurosci. 27, 723-749. doi: 10.1146/annurev.neuro.27.070203.144244
23. Bsibsi, M., Ravid, R., Gveric, D., and Van Noort, J. M. (2002). Broad expression of Toll-like receptors in the human central nervous system. J. Neuropathol. Exp. Neurol. 61, 1013-1021.
24. Bukauskas, F. F., Jordan, K., Bukauskiene, A., Bennett, M. V., Lampe, P. D., Laird, D. W., et al. (2000). Clustering of connexin 43-enhanced green fluorescent protein gap junction channels and functional coupling in living cells. Proc. Natl. Acad. Sci. U.S.A. 97, 2556-2561. doi: 10.1073/pnas.050588497
25. Burkovetskaya, M., Karpuk, N., Xiong, J., Bosch, M., Boska, M. D., Takeuchi, H., et al. (2014). Evidence for Aberrant Astrocyte Hemichannel Activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). PLoS ONE 9:e95023. doi: 10.1371/journal.pone.0095023
26. Cagnin, A., Brooks, D. J., Kennedy, A. M., Gunn, R. N., Myers, R., Turkheimer, F. E., et al. (2001). In-vivo measurement of activated microglia in dementia. Lancet 358, 461-467. doi: 10.1016/S0140-6736(01)05625-2
27. Carpentier, P. A., Duncan, D. S., and Miller, S. D. (2008). Glial toll-like receptor signaling in central nervous system infection and autoimmunity. Brain Behav. Immun. 22, 140-147. doi: 10.1016/j.bbi.2007.08.011
28. Chang, Q., Gonzalez, M., Pinter, M. J., and Balice-Gordon, R. J. (1999). Gap junctional coupling and patterns of connexin expression among neonatal rat lumbar spinal motor neurons. J. Neurosci. 19, 10813-10828.
29. Charles, A. (1998). Intercellular calcium waves in glia. Glia 24, 39-49. doi: 10.1002/(SICI)1098-1136(199809)24:1<39::AID-GLIA5>3.0.CO;2-W
30. Cho, S., Park, E. M., Febbraio, M., Anrather, J., Park, L., Racchumi, G., et al. (2005). The class B scavenger receptor CD36 mediates free radical production and tissue injury in cerebral ischemia. J. Neurosci. 25, 2504-2512. doi: 10.1523/JNEUROSCI.0035-05.2005
31. Christie, M. J., Williams, J. T., and North, R. A. (1989). Electrical coupling synchronizes subthreshold activity in locus coeruleus neurons in vitro from neonatal rats. J. Neurosci. 9, 3584-3589.
32. Contreras, J. E., Saez, J. C., Bukauskas, F. F., and Bennett, M. V. (2003). Gating and regulation of connexin 43 (Cx43) hemichannels. Proc. Natl. Acad. Sci. U.S.A. 100, 11388-11393. doi: 10.1073/pnas.1434298100
33. Coraci, I. S., Husemann, J., Berman, J. W., Hulette, C., Dufour, J. H., Campanella, G. K., et al. (2002). CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am. J. Pathol. 160, 101-112. doi: 10.1016/S0002-9440(10)64354-4
34. Cui, Y., Masaki, K., Yamasaki, R., Imamura, S., Suzuki, S. O., Hayashi, S., et al. (2014). Extensive dysregulations of oligodendrocytic and astrocytic connexins are associated with disease progression in an amyotrophic lateral sclerosis mouse model. J. Neuroinflammation 11:42. doi: 10.1186/1742-2094-11-42
35. Dahl, G., and Locovei, S. (2006). Pannexin: to gap or not to gap, is that a question? IUBMB Life 58, 409-419. doi: 10.1080/15216540600794526
36. Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., et al. (2005). ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752-758. doi: 10.1038/nn1472
37. Deans, M. R., Gibson, J. R., Sellitto, C., Connors, B. W., and Paul, D. L. (2001). Synchronous activity of inhibitory networks in neocortex requires electrical synapses containing connexin36. Neuron 31, 477-485. doi: 10.1016/S08966273(01)00373-7
38. Delisle, M. B., and Carpenter, S. (1984). Neurofibrillary axonal swellings and amyotrophic lateral sclerosis. J. Neurol. Sci. 63, 241-250. doi: 10.1016/0022-510X(84)90199-0
39. Del Rio-Hortega, P. (1932). Cytology and Cellular Pathology of the Nervous System. New York, NY: Penfield Wed.
40. De Pina-Benabou, M. H., Szostak, V., Kyrozis, A., Rempe, D., Uziel, D., UrbanMaldonado, M., et al. (2005). Blockade of gap junctions in vivo provides neuroprotection after perinatal global ischemia. Stroke 36, 2232-2237. doi: 10.1161/01.STR.0000182239.75969.d8
41. Dermietzel, R., Gao, Y., Scemes, E., Vieira, D., Urban, M., Kremer, M., et al. (2000). Connexin43 null mice reveal that astrocytes express multiple connexins. Brain Res. Brain Res. Rev. 32, 45-56. doi: 10.1016/S0165-0173(99)00067-3
42. Dermietzel, R., Hertberg, E. L., Kessler, J. A., and Spray, D. C. (1991). Gap junctions between cultured astrocytes: immunocytochemical, molecular, and electrophysiological analysis. J. Neurosci. 11, 1421-1432.
43. Dermietzel, R., Traub, O., Hwang, T. K., Beyer, E., Bennett, M. V., Spray, D. C., et al. (1989). Differential expression of three gap junction proteins in developing and mature brain tissues. Proc. Natl. Acad. Sci. U.S.A. 86, 10148-10152. doi: 10.1073/pnas.86.24.10148
44. De Vuyst, E., Decrock, E., De Bock, M., Yamasaki, H., Naus, C. C., Evans, W. H., et al. (2007). Connexin hemichannels and gap junction channels are differentially influenced by lipopolysaccharide and basic fibroblast growth factor. Mol. Biol. Cell 18, 34-46. doi: 10.1091/mbc.E06-03-0182
45. Dickson, T. C., King, C. E., McCormack, G. H., and Vickers, J. C. (1999). Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer's disease. Exp. Neurol. 156, 100-110. doi: 10.1006/exnr.1998.7010
46. Dutta, R., and Trapp, B. D. (2007). Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology 68, S22-S31; discussion S43-S54.
47. Eikelenboom, P., Bate, C., Van Gool, W. A., Hoozemans, J. J., Rozemuller, J. M., Veerhuis, R., et al. (2002). Neuroinflammation in Alzheimer's disease and prion disease. Glia 40, 232-239. doi: 10.1002/glia.10146
48. El Khoury, J., Hickman, S. E., Thomas, C. A., Cao, L., Silverstein, S. C., and Loike, J. D. (1996). Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382, 716-719. doi: 10.1038/382716a0
49. El Khoury, J., Hickman, S. E., Thomas, C. A., Loike, J. D., and Silverstein, S. C. (1998). Microglia, scavenger receptors, and the pathogenesis of Alzheimer's disease. Neurobiol. Aging 19, S81-S84. doi: 10.1016/S0197-4580(98)00036-0
50. Eugenin, E. A., Basilio, D., Saez, J. C., Orellana, J. A., Raine, C. S., Bukauskas, F., et al. (2012). The role of gap junction channels during physiologic and pathologic conditions of the human central nervous system. J. Neuroimmune Pharmacol. 7, 499-518. doi: 10.1007/s11481-012-9352-5
51. Eugenin, E. A., and Berman, J. W. (2013). Cytochrome c dysregulation induced by HIV infection of astrocytes results in bystander apoptosis of uninfected astrocytes by an IP3 and calcium-dependent mechanism. J. Neurochem. 127, 644-651. doi: 10.1111/jnc.12443
52. Eugenin, E. A., Eckardt, D., Theis, M., Willecke, K., Bennett, M. V., and Saez, J. C. (2001). Microglia at brain stab wounds express connexin 43 and in vitro form functional gap junctions after treatment with interferon-gamma and tumor necrosis factor-alpha. Proc. Natl. Acad. Sci. U.S.A. 98, 4190-4195. doi: 10.1073/pnas.051634298
53. Frank, M., Eiberger, B., Janssen-Bienhold, U., De Sevilla Muller, L. P., Tjarks, A., Kim, J. S., et al. (2010). Neuronal connexin-36 can functionally replace connexin-45 in mouse retina but not in the developing heart. J. Cell Sci. 123, 3605-3615. doi: 10.1242/jcs.068668
54. Frantseva, M. V., Kokarovtseva, L., and Perez Velazquez, J. L. (2002). Ischemiainduced brain damage depends on specific gap-junctional coupling. J. Cereb. Blood Flow Metab. 22, 453-462. doi: 10.1097/00004647-200204000-00009
55. Fushiki, S., Perez Velazquez, J. L., Zhang, L., Bechberger, J. F., Carlen, P. L., and Naus, C. C. (2003). Changes in neuronal migration in neocortex of connexin43 null mutant mice. J. Neuropathol. Exp. Neurol. 62, 304-314.
56. Gaietta, G., Deerinck, T. J., Adams, S. R., Bouwer, J., Tour, O., Laird, D. W., et al. (2002). Multicolor and electron microscopic imaging of connexin trafficking. Science 296, 503-507. doi: 10.1126/science.1068793
57. Garg, S., Md Syed, M., and Kielian, T. (2005). Staphylococcus aureus-derived peptidoglycan induces Cx43 expression and functional gap junction intercellular communication in microglia. J. Neurochem. 95, 475-483. doi: 10.1111/j.1471-4159.2005.03384.x
58. Ghezzi, P., and Mennini, T. (2001). Tumor necrosis factor and motoneuronal degeneration: an open problem. Neuroimmunomodulation 9, 178-182. doi: 10.1159/000049024
59. Giaume, C., Tabernero, A., and Medina, J. M. (1997). Metabolic trafficking through astrocytic gap junctions. Glia 21, 114-123. doi: 10.1002/(SICI)1098-1136(199709)21:1<114::AID-GLIA13>3.0.CO;2-V
60. Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C., and Gage, F. H. (2010). Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918-934. doi: 10.1016/j.cell.2010.02.016
61. Goel, S., Wharton, S. B., Brett, L. P., and Whittle, I. R. (2003). Morphological changes and stress responses in neurons in cerebral cortex infiltrated by diffuse astrocytoma. Neuropathology 23, 262-270. doi: 10.1046/j.1440-1789.2003.00510.x
62. Goldberg, G. S., Lampe, P. D., and Nicholson, B. J. (1999). Selective transfer of endogenous metabolites through gap junctions composed of different connexins. Nat. Cell Biol. 1, 457-459. doi: 10.1038/15693
63. Goldberg, G. S., Moreno, A. P., and Lampe, P. D. (2002). Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP. J. Biol. Chem. 277, 36725-36730. doi: 10.1074/jbc.M109797200
64. Goldberg, G. S., Valiunas, V., and Brink, P. R. (2004). Selective permeability of gap junction channels. Biochim. Biophys. Acta 1662, 96-101. doi: 10.1016/j.bbamem.2003.11.022
65. Grewal, R. P., Yoshida, T., Finch, C. E., and Morgan, T. E. (1997). Scavenger receptor mRNAs in rat brain microglia are induced by kainic acid lesioning and by cytokines. Neuroreport 8, 1077-1081. doi: 10.1097/00001756-199703240-00003
66. Harris, A. L. (2001). Emerging issues of connexin channels: biophysics fills the gap. Q. Rev. Biophys. 34, 325-472. doi: 10.1017/S0033583501003705
67. Harris, A. L. (2007). Connexin channel permeability to cytoplasmic molecules. Prog. Biophys. Mol. Biol. 94, 120-143. doi: 10.1016/j.pbiomolbio.2007.03.011
68. Hartfield, E. M., Rinaldi, F., Glover, C. P., Wong, L. F., Caldwell, M. A., and Uney, J. B. (2011). Connexin 36 expression regulates neuronal differentiation from neural progenitor cells. PLoS ONE 6:e14746. doi: 10.1371/journal.pone.0014746
69. Henkel, J. S., Beers, D. R., Zhao, W., and Appel, S. H. (2009). Microglia in ALS: the good, the bad, and the resting. J. Neuroimmune Pharmacol. 4, 389-398. doi: 10.1007/s11481-009-9171-5
70. Herman, M. A., and Jahr, C. E. (2007). Extracellular glutamate concentration in hippocampal slice. J. Neurosci. 27, 9736-9741. doi: 10.1523/JNEUROSCI.3009-07.2007
71. Hori, N., and Carpenter, D. O. (1994). Functional and morphological changes induced by transient in vivo ischemia. Exp. Neurol. 129, 279-289. doi: 10.1006/exnr.1994.1170
72. Hormuzdi, S. G., Pais, I., Lebeau, F. E., Towers, S. K., Rozov, A., Buhl, E. H., et al. (2001). Impaired electrical signaling disrupts gamma frequency oscillations in connexin 36-deficient mice. Neuron 31, 487-495. doi: 10.1016/S0896-6273(01)00387-7
73. Huang, C., Han, X., Li, X., Lam, E., Peng, W., Lou, N., et al. (2012). Critical role of connexin 43 in secondary expansion of traumatic spinal cord injury. J. Neurosci. 32, 3333-3338. doi: 10.1523/JNEUROSCI.1216-11.2012
74. Hunter, A. W., Jourdan, J., and Gourdie, R. G. (2003). Fusion of GFP to the carboxyl terminus of connexin43 increases gap junction size in HeLa cells. Cell Commun. Adhes. 10, 211-214. doi: 10.1080/714040429
75. Iribarren, P., Chen, K., Hu, J., Gong, W., Cho, E. H., Lockett, S., et al. (2005). CpGcontaining oligodeoxynucleotide promotes microglial cell uptake of amyloid beta 1-42 peptide by up-regulating the expression of the G-proteincoupled receptor mFPR2. FASEB J. 19, 2032-2034.
76. Jefferys, J. G. (1995). Nonsynaptic modulation of neuronal activity in the brain: electric currents and extracellular ions. Physiol. Rev. 75, 689-723.
77. Jimenez, S., Baglietto-Vargas, D., Caballero, C., Moreno-Gonzalez, I., Torres, M., Sanchez-Varo, R., et al. (2008). Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease: age-dependent switch in the microglial phenotype from alternative to classic. J. Neurosci. 28, 11650-11661. doi: 10.1523/JNEUROSCI.3024-08.2008
78. Kalogeris, T., Baines, C. P., Krenz, M., and Korthuis, R. J. (2012). Cell biology of ischemia/reperfusion injury. Int. Rev. Cell Mol. Biol. 298, 229-317. doi: 10.1016/B978-0-12-394309-5.00006-7
79. Kamata, H., Honda, S., Maeda, S., Chang, L., Hirata, H., and Karin, M. (2005). Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120, 649-661. doi: 10.1016/j.cell.2004.12.041
80. Kawanokuchi, J., Mizuno, T., Takeuchi, H., Kato, H., Wang, J., Mitsuma, N., et al. (2006). Production of interferon-gamma by microglia. Mult. Scler. 12, 558-564. doi: 10.1177/1352458506070763
81. Kawasaki, A., Hayashi, T., Nakachi, K., Trosko, J. E., Sugihara, K., Kotake, Y., et al. (2009). Modulation of connexin 43 in rotenone-induced model of Parkinson's disease. Neuroscience 160, 61-68. doi: 10.1016/j.neuroscience.2009.01.080
82. Kempermann, G., and Neumann, H. (2003). Neuroscience. Microglia: the enemy within? Science 302, 1689-1690. doi: 10.1126/science.1092864
83. Kielian, T. (2008). Glial connexins and gap junctions in CNS inflammation and disease. J. Neurochem. 106, 1000-1016. doi: 10.1111/j.1471-4159.2008.05405.x
84. Kipnis, J., Avidan, H., Caspi, R. R., and Schwartz, M. (2004). Dual effect of CD4+CD25+ regulatory T cells in neurodegeneration: a dialogue with microglia. Proc. Natl. Acad. Sci. U.S.A. 101(Suppl. 2), 14663-14669. doi: 10.1073/pnas.0404842101
85. Knieps, M., Herrmann, S., Lehmann, C., Loer, B., Hoch, M., and Famulok, M. (2007). Anti-innexin 2 aptamers specifically inhibit the heterologous interaction of the innexin 2 and innexin 3 carboxyl-termini in vitro. Biol. Chem. 388, 561-568. doi: 10.1515/BC.2007.074
86. Koenigsknecht, J., and Landreth, G. (2004). Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism. J. Neurosci. 24, 9838-9846. doi: 10.1523/JNEUROSCI.2557-04.2004
87. Koulakoff, A., Mei, X., Orellana, J. A., Saez, J. C., and Giaume, C. (2012). Glial connexin expression and function in the context of Alzheimer's disease. Biochim. Biophys. Acta 1818, 2048-2057. doi: 10.1016/j.bbamem.2011.10.001
88. Kreutzberg, G. W. (1996). Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312-318. doi: 10.1016/0166-2236(96)10049-7
89. Laird, D. W. (2006). Life cycle of connexins in health and disease. Biochem. J. 394, 527-543. doi: 10.1042/BJ20051922
90. Laird, D. W. (2010). The gap junction proteome and its relationship to disease. Trends Cell Biol. 20, 92-101. doi: 10.1016/j.tcb.2009.11.001
91. Lawson, L. J., Perry, V. H., Dri, P., and Gordon, S. (1990). Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39, 151-170. doi: 10.1016/0306-4522(90)90229-W
92. Leithe, E., and Rivedal, E. (2007). Ubiquitination of gap junction proteins. J. Membr. Biol. 217, 43-51. doi: 10.1007/s00232-007-9050-z
93. Liang, J., Takeuchi, H., Doi, Y., Kawanokuchi, J., Sonobe, Y., Jin, S., et al. (2008). Excitatory amino acid transporter expression by astrocytes is neuroprotective against microglial excitotoxicity. Brain Res. 1210, 11-19. doi: 10.1016/j.brainres.2008.03.012
94. Liang, J., Takeuchi, H., Jin, S., Noda, M., Li, H., Doi, Y., et al. (2010). Glutamate induces neurotrophic factor production from microglia via protein kinase C pathway. Brain Res. 1322, 8-23. doi: 10.1016/j.brainres.2010.01.083
95. Liu, Y., Walter, S., Stagi, M., Cherny, D., Letiembre, M., Schulz-Schaeffer, W., et al. (2005). LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide. Brain 128, 1778-1789. doi: 10.1093/brain/awh531
96. Lo, C. W., Waldo, K. L., and Kirby, M. L. (1999). Gap junction communication and the modulation of cardiac neural crest cells. Trends Cardiovasc. Med. 9, 63-69. doi: 10.1016/S1050-1738(99)00015-8
97. Lobsiger, C. S., and Cleveland, D. W. (2007). Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat. Neurosci. 10, 1355-1360. doi: 10.1038/nn1988
98. Lopez, P., Balicki, D., Buehler, L. K., Falk, M. M., and Chen, S. C. (2001). Distribution and dynamics of gap junction channels revealed in living cells. Cell Commun. Adhes. 8, 237-242. doi: 10.3109/15419060109080730
99. Lutz, S. E., Raine, C. S., and Brosnan, C. F. (2012). Loss of astrocyte connexins 43 and 30 does not significantly alter susceptibility or severity of acute experimental autoimmune encephalomyelitis in mice. J. Neuroimmunol. 245, 8-14. doi: 10.1016/j.jneuroim.2012.01.007
100. Mantovani, A., Sozzani, S., Locati, M., Allavena, P., and Sica, A. (2002). Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23, 549-555. doi: 10.1016/S1471-4906(02)02302-5
101. Marin-Teva, J. L., Dusart, I., Colin, C., Gervais, A., Van Rooijen, N., and Mallat, M. (2004). Microglia promote the death of developing Purkinje cells. Neuron 41, 535-547. doi: 10.1016/S0896-6273(04)00069-8
102. Markoullis, K., Sargiannidou, I., Gardner, C., Hadjisavvas, A., Reynolds, R., and Kleopa, K. A. (2012). Disruption of oligodendrocyte gap junctions in experimental autoimmune encephalomyelitis. Glia 60, 1053-1066. doi: 10.1002/glia.22334
103. Masaki, K., Suzuki, S. O., Matsushita, T., Yonekawa, T., Matsuoka, T., Isobe, N., et al. (2012). Extensive loss of connexins in Balo's disease: evidence for an auto-antibody-independent astrocytopathy via impaired astrocyteoligodendrocyte/myelin interaction. Acta Neuropathol. 123, 887-900. doi: 10.1007/s00401-012-0972-x
104. Matsushita, T., Masaki, K., Suzuki, S., Matsuoka, T., Yonekawa, T., Wu, X. M., et al. (2011). Astrocytopathy in neuromyelitis optica, multiple sclerosis and Balo's disease. Rinsho Shinkeigaku 51, 898-900. doi: 10.5692/clinicalneurol.51.898
105. Mattila, P. M., Rinne, J. O., Helenius, H., and Roytta, M. (1999). Neuritic degeneration in the hippocampus and amygdala in Parkinson's disease in relation to Alzheimer pathology. Acta Neuropathol. 98, 157-164. doi: 10.1007/s004010051064
106. McGeer, P. L., and McGeer, E. G. (2002). Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 26, 459-470. doi: 10.1002/mus.10191
107. Menichella, D. M., Goodenough, D. A., Sirkowski, E., Scherer, S. S., and Paul, D. L. (2003). Connexins are critical for normal myelination in the CNS. J. Neurosci. 23, 5963-5973.
108. Menichella, D. M., Majdan, M., Awatramani, R., Goodenough, D. A., Sirkowski, E., Scherer, S. S., et al. (2006). Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity. J. Neurosci. 26, 10984-10991. doi: 10.1523/JNEUROSCI.0304-06.2006
109. Mizuno, T., Zhang, G., Takeuchi, H., Kawanokuchi, J., Wang, J., Sonobe, Y., et al. (2008). Interferon-gamma directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFN-gamma receptor and AMPA GluR1 receptor. FASEB J. 22, 1797-1806. doi: 10.1096/fj.07-099499
110. Nadarajah, B., Thomaidou, D., Evans, W. H., and Parnavelas, J. G. (1996). Gap junctions in the adult cerebral cortex: regional differences in their distribution and cellular expression of connexins. J. Comp. Neurol. 376, 326-342. doi: 10.1002/(SICI)1096-9861(19961209)376:2<326::AID-CNE13>3.0.CO;2-J
111. Nagy, J. I., Ionescu, A. V., Lynn, B. D., and Rash, J. E. (2003). Coupling of astrocyte connexins Cx26, Cx30, Cx43 to oligodendrocyte Cx29, Cx32, Cx47: implications from normal and connexin32 knockout mice. Glia 44, 205-218. doi: 10.1002/glia.10278
112. Nagy, J. I., and Rash, J. E. (2000). Connexins and gap junctions of astrocytes and oligodendrocytes in the CNS. Brain Res. Brain Res. Rev. 32, 29-44. doi: 10.1016/S0165-0173(99)00066-1
113. Nakanishi, H., and Wu, Z. (2009). Microglia-aging: roles of microglial lysosomeand mitochondria-derived reactive oxygen species in brain aging. Behav. Brain Res. 201, 1-7. doi: 10.1016/j.bbr.2009.02.001
114. Naus, C. C., Bechberger, J. F., Zhang, Y., Venance, L., Yamasaki, H., Juneja, S. C., et al. (1997). Altered gap junctional communication, intercellular signaling, and growth in cultured astrocytes deficient in connexin43. J. Neurosci. Res. 49, 528-540. doi: 10.1002/(SICI)1097-4547(19970901)49:5<528::AIDJNR3>3.0.CO;2-D
115. Nelson, P. T., Soma, L. A., and Lavi, E. (2002). Microglia in diseases of the central nervous system. Ann. Med. 34, 491-500. doi: 10.1080/078538902321117698
116. Newsholme, E. A., and Calder, P. C. (1997). The proposed role of glutamine in some cells of the immune system and speculative consequences for the whole animal. Nutrition 13, 728-730. doi: 10.1016/S0899-9007(97)83034-1
117. Newsholme, P., and Newsholme, E. A. (1989). Rates of utilization of glucose, glutamine and oleate and formation of end-products by mouse peritoneal macrophages in culture. Biochem. J. 261, 211-218.
118. Nimmerjahn, A., Kirchhoff, F., and Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314-1318. doi: 10.1126/science.1110647
119. Nissim, I. (1999). Newer aspects of glutamine/glutamate metabolism: the role of acute pH changes. Am. J. Physiol. 277, F493-F497.
120. Odermatt, B., Wellershaus, K., Wallraff, A., Seifert, G., Degen, J., Euwens, C., et al. (2003). 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. 23, 4549-4559.
121. Orellana, J. A., Saez, J. C., Bennett, M. V., Berman, J. W., Morgello, S., and Eugenin, E. A. (2014). HIV increases the release of dickkopf-1 protein from human astrocytes by a Cx43 hemichannel-dependent mechanism. J. Neurochem. 128, 752-763. doi: 10.1111/jnc.12492
122. Orellana, J. A., Saez, P. J., Shoji, K. F., Schalper, K. A., Palacios-Prado, N., Velarde, V., et al. (2009). Modulation of brain hemichannels and gap junction channels by pro-inflammatory agents and their possible role in neurodegeneration. Antioxid. Redox Signal. 11, 369-399. doi: 10.1089/ars.2008.2130
123. Orellana, J. A., Shoji, K. F., Abudara, V., Ezan, P., Amigou, E., Saez, P. J., et al. (2011). Amyloid beta-induced death in neurons involves glial and neuronal hemichannels. J. Neurosci. 31, 4962-4977. doi: 10.1523/JNEUROSCI.6417-10.2011
124. Orr, C. F., Rowe, D. B., and Halliday, G. M. (2002). An inflammatory review of Parkinson's disease. Prog. Neurobiol. 68, 325-340. doi: 10.1016/S0301-0082(02)00127-2
125. Orthmann-Murphy, J. L., Freidin, M., Fischer, E., Scherer, S. S., and Abrams, C. K. (2007). Two distinct heterotypic channels mediate gap junction coupling between astrocyte and oligodendrocyte connexins. J. Neurosci. 27, 13949-13957. doi: 10.1523/JNEUROSCI.3395-07.2007
126. Parenti, R., Campisi, A., Vanella, A., and Cicirata, F. (2002). Immunocytochemical and RT-PCR analysis of connexin36 in cultures of mammalian glial cells. Arch. Ital. Biol. 140, 101-108.
127. Parsons, C. G., Stoffler, A., and Danysz, W. (2007). Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system-too little activation is bad, too much is even worse. Neuropharmacology 53, 699-723. doi: 10.1016/j.neuropharm.2007.07.013
128. Paul, D. L. (1995). New functions for gap junctions. Curr. Opin. Cell Biol. 7, 665-672. doi: 10.1016/0955-0674(95)80108-1
129. Pavese, N., Gerhard, A., Tai, Y. F., Ho, A. K., Turkheimer, F., Barker, R. A., et al. (2006). Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Neurology 66, 1638-1643. doi: 10.1212/01.wnl.0000222734.56412.17
130. Pavlidis, M., Stupp, T., Naskar, R., Cengiz, C., and Thanos, S. (2003). Retinal ganglion cells resistant to advanced glaucoma: a postmortem study of human retinas with the carbocyanine dye DiI. Invest. Ophthalmol. Vis. Sci. 44, 5196-5205. doi: 10.1167/iovs.03-0614
131. Piani, D., Spranger, M., Frei, K., Schaffner, A., and Fontana, A. (1992). Macrophage-induced cytotoxicity of N-methyl-D-aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines. Eur. J. Immunol. 22, 2429-2436. doi: 10.1002/eji.1830220936
132. Pontikis, C. C., Cotman, S. L., Macdonald, M. E., and Cooper, J. D. (2005). Thalamocortical neuron loss and localized astrocytosis in the Cln3Deltaex7/8 knock-in mouse model of Batten disease. Neurobiol. Dis. 20, 823-836. doi: 10.1016/j.nbd.2005.05.018
133. Ransom, B., Behar, T., and Nedergaard, M. (2003). New roles for astrocytes (stars at last). Trends Neurosci. 26, 520-522. doi: 10.1016/j.tins.2003.08.006
134. Rash, J. E., Olson, C. O., Davidson, K. G., Yasumura, T., Kamasawa, N., and Nagy, J. I. (2007). Identification of connexin36 in gap junctions between neurons in rodent locus coeruleus. Neuroscience 147, 938-956. doi: 10.1016/j.neuroscience.2007.04.061
135. Rash, J. E., Yasumura, T., Dudek, F. E., and Nagy, J. I. (2001). Cell-specific expression of connexins and evidence of restricted gap junctional coupling between glial cells and between neurons. J. Neurosci. 21, 1983-2000.
136. Rawanduzy, A., Hansen, A., Hansen, T. W., and Nedergaard, M. (1997). Effective reduction of infarct volume by gap junction blockade in a rodent model of stroke. J. Neurosurg. 87, 916-920. doi: 10.3171/jns.1997.87.6.0916
137. Retamal, M. A., Schalper, K. A., Shoji, K. F., Bennett, M. V., and Saez, J. C. (2007). Opening of connexin 43 hemichannels is increased by lowering intracellular redox potential. Proc. Natl. Acad. Sci. U.S.A. 104, 8322-8327. doi: 10.1073/pnas.0702456104
138. Richard, K. L., Filali, M., Prefontaine, P., and Rivest, S. (2008). Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer's disease. J. Neurosci. 28, 5784-5793. doi: 10.1523/JNEUROSCI.1146-08.2008
139. Rock, R. B., Gekker, G., Hu, S., Sheng, W. S., Cheeran, M., Lokensgard, J. R., et al. (2004). Role of microglia in central nervous system infections. Clin. Microbiol. Rev. 17, 942-964. doi: 10.1128/CMR.17.4.942-964.2004
140. Rouach, N., Avignone, E., Meme, W., Koulakoff, A., Venance, L., Blomstrand, F., et al. (2002). Gap junctions and connexin expression in the normal and pathological central nervous system. Biol. Cell 94, 457-475. doi: 10.1016/S02484900(02)00016-3
141. Rouach, N., Koulakoff, A., Abudara, V., Willecke, K., and Giaume, C. (2008). Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322, 1551-1555. doi: 10.1126/science.1164022
142. Rufer, M., Wirth, S. B., Hofer, A., Dermietzel, R., Pastor, A., Kettenmann, H., et al. (1996). Regulation of connexin-43, GFAP, and FGF-2 is not accompanied by changes in astroglial coupling in MPTP-lesioned, FGF-2-treated parkinsonian mice. J. Neurosci. Res. 46, 606-617. doi: 10.1002/(SICI)1097-4547(19961201)46:5<606::AID-JNR9>3.0.CO;2-N
143. Saez, J. C., Berthoud, V. M., Branes, M. C., Martinez, A. D., and Beyer, E. C. (2003). Plasma membrane channels formed by connexins: their regulation and functions. Physiol. Rev. 83, 1359-1400.
144. Saito, Y., Kawashima, A., Ruberu, N. N., Fujiwara, H., Koyama, S., Sawabe, M., et al. (2003). Accumulation of phosphorylated alpha-synuclein in aging human brain. J. Neuropathol. Exp. Neurol. 62, 644-654.
145. Sawada, M. (2009). Neuroprotective and toxic changes in microglia in neurodegenerative disease. Parkinsonism. Relat. Disord. 15(Suppl. 1), S39-S41. doi: 10.1016/S1353-8020(09)70011-2
146. Scemes, E., Dermietzel, R., and Spray, D. C. (1998). Calcium waves between astrocytes from Cx43 knockout mice. Glia 24, 65-73. doi: 10.1002/(SICI)1098-1136(199809)24:1<65::AID-GLIA7>3.0.CO;2-#
147. Schwab, J. M., and Schluesener, H. J. (2004). Microglia rules: insights into microglial-neuronal signaling. Cell Death Differ. 11, 1245-1246. doi: 10.1038/sj.cdd.4401487
148. Schwartz, M., Shaked, I., Fisher, J., Mizrahi, T., and Schori, H. (2003). Protective autoimmunity against the enemy within: fighting glutamate toxicity. Trends Neurosci. 26, 297-302. doi: 10.1016/S0166-2236(03)00126-7
149. Seabrook, T. J., Jiang, L., Maier, M., and Lemere, C. A. (2006). Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice. Glia 53, 776-782. doi: 10.1002/glia.20338
150. Simard, A. R., Soulet, D., Gowing, G., Julien, J. P., and Rivest, S. (2006). Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49, 489-502. doi: 10.1016/j.neuron.2006.01.022
151. Sohl, G., Maxeiner, S., and Willecke, K. (2005). Expression and functions of neuronal gap junctions. Nat. Rev. Neurosci. 6, 191-200. doi: 10.1038/nrn1627
152. Solan, J. L., and Lampe, P. D. (2009). Connexin43 phosphorylation: structural changes and biological effects. Biochem. J. 419, 261-272. doi: 10.1042/BJ20082319
153. Stirling, D. P., Khodarahmi, K., Liu, J., McPhail, L. T., McBride, C. B., Steeves, J. D., et al. (2004). Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J. Neurosci. 24, 2182-2190. doi: 10.1523/JNEUROSCI.5275-03.2004
154. Sung, J. Y., Lee, H. J., Jeong, E. I., Oh, Y., Park, J., Kang, K. S., et al. (2007). Alpha-synuclein overexpression reduces gap junctional intercellular communication in dopaminergic neuroblastoma cells. Neurosci. Lett. 416, 289-293. doi: 10.1016/j.neulet.2007.02.025
155. Sutor, B., Schmolke, C., Teubner, B., Schirmer, C., and Willecke, K. (2000). Myelination defects and neuronal hyperexcitability in the neocortex of connexin 32-deficient mice. Cereb. Cortex 10, 684-697. doi: 10.1093/cercor/10.7.684
156. Suzuki, H., Ono, K., and Sawada, M. (2014). Protective effect of INI-0602, a gap junction inhibitor, on dopaminergic neurodegeneration of mice with unilateral 6-hydroxydopamine injection. J. Neural Transm. doi: 10.1007/s00702-0141209-z. [Epub ahead of print].
157. Suzumura, A., Mezitis, S. G., Gonatas, N. K., and Silberberg, D. H. (1987). MHC antigen expression on bulk isolated macrophage-microglia from newborn mouse brain: induction of Ia antigen expression by gamma-interferon. J. Neuroimmunol. 15, 263-278. doi: 10.1016/0165-5728(87)90121-4
158. Swann, J. W., Al-Noori, S., Jiang, M., and Lee, C. L. (2000). Spine loss and other dendritic abnormalities in epilepsy. Hippocampus 10, 617-625. doi: 10.1002/1098-1063(2000)10:5<617::AID-HIPO13>3.0.CO;2-R
159. Tabernero, A., Medina, J. M., and Giaume, C. (2006). Glucose metabolism and proliferation in glia: role of astrocytic gap junctions. J. Neurochem. 99, 1049-1061. doi: 10.1111/j.1471-4159.2006.04088.x
160. Takahashi, T., Yagishita, S., Amano, N., Yamaoka, K., and Kamei, T. (1997). Amyotrophic lateral sclerosis with numerous axonal spheroids in the corticospinal tract and massive degeneration of the cortex. Acta Neuropathol. 94, 294-299. doi: 10.1007/s004010050707
161. Takaki, J., Fujimori, K., Miura, M., Suzuki, T., Sekino, Y., and Sato, K. (2012). L-glutamate released from activated microglia downregulates astrocytic Lglutamate transporter expression in neuroinflammation: the 'collusion' hypothesis for increased extracellular L-glutamate concentration in neuroinflammation. J. Neuroinflammation 9:275. doi: 10.1186/1742-2094-9-275
162. Takeuchi, H. (2010). Neurotoxicity by microglia: mechanisms and potential therapeutic strategy. Clin. Exp. Neuroimmunol. 1, 12-21. doi: 10.1111/j.17591961.2009.00001.x
163. Takeuchi, H., Jin, S., Suzuki, H., Doi, Y., Liang, J., Kawanokuchi, J., et al. (2008a). Blockade of microglial glutamate release protects against ischemic brain injury. Exp. Neurol. 214, 144-146. doi: 10.1016/j.expneurol.2008.08.001
164. Takeuchi, H., Jin, S., Suzuki, H., Doi, Y., Liang, J., Kawanokuchi, J., et al. (2008b). Blockade of microglial glutamate release protects against ischemic brain injury. Exp. Neurol. 214, 144-146. doi: 10.1016/j.expneurol.2008.08.001
165. Takeuchi, H., Jin, S., Wang, J., Zhang, G., Kawanokuchi, J., Kuno, R., et al. (2006). Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J. Biol. Chem. 281, 21362-21368. doi: 10.1074/jbc.M600504200
166. Takeuchi, H., Kawanokuchi, J., Mizuno, T., and Suzumura, A. (2014). Expression profile of connexins in the central nervous system. Clini. Exp. Neuroimmunol. doi: 10.1111/cen3.12106. [Epub ahead of print].
167. Takeuchi, H., Mizoguchi, H., Doi, Y., Jin, S., Noda, M., Liang, J., et al. (2011). Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease. PLoS ONE 6:e21108. doi: 10.1371/journal.pone.0021108
168. Takeuchi, H., Mizuno, T., Zhang, G., Wang, J., Kawanokuchi, J., Kuno, R., et al. (2005). Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. J. Biol. Chem. 280, 10444-10454. doi: 10.1074/jbc.M413863200
169. Talaveron, R., Matarredona, E. R., De La Cruz, R. R., Macias, D., Galvez, V., and Pastor, A. M. (2014). Implanted neural progenitor cells regulate glial reaction to brain injury and establish gap junctions with host glial cells. Glia 62, 623-638. doi: 10.1002/glia.22630
170. Tamura, K., Alessandri, B., Heimann, A., and Kempski, O. (2011). The effect of a gap-junction blocker, carbenoxolone, on ischemic brain injury and cortical spreading depression. Neuroscience 194, 262-271. doi: 10.1016/j.neuroscience.2011.07.043
171. Teubner, B., Michel, V., Pesch, J., Lautermann, J., Cohen-Salmon, M., Sohl, G., et al. (2003). Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of endocochlear potential. Hum. Mol. Genet. 12, 13-21. doi: 10.1093/hmg/ddg001
172. Teubner, B., Odermatt, B., Guldenagel, M., Sohl, G., Degen, J., Bukauskas, F., et al. (2001). Functional expression of the new gap junction gene connexin47 transcribed in mouse brain and spinal cord neurons. J. Neurosci. 21, 1117-1126.
173. Thompson, R. J., Zhou, N., and Macvicar, B. A. (2006). Ischemia opens neuronal gap junction hemichannels. Science 312, 924-927. doi: 10.1126/science.1126241
174. Trapp, B. D., Peterson, J., Ransohoff, R. M., Rudick, R., Mork, S., and Bo, L. (1998). Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278-285. doi: 10.1056/NEJM199801293380502
175. Tsacopoulos, M., and Magistretti, P. J. (1996). Metabolic coupling between glia and neurons. J. Neurosci. 16, 877-885.
176. Umebayashi, D., Natsume, A., Takeuchi, H., Hara, M., Nishimura, Y., Fukuyama, R., et al. (2014). Blockade of gap junction hemichannel protects secondary spinal cord injury from activated microglia-mediated glutamate exitoneurotoxicity. J. Neurotrauma. doi: 10.1089/neu.2013.3223. [Epub ahead of print].
177. Upender, M. B., and Naegele, J. R. (1999). Activation of microglia during developmentally regulated cell death in the cerebral cortex. Dev. Neurosci. 21, 491-505. doi: 10.1159/000017416
178. Valcour, V., Sithinamsuwan, P., Letendre, S., and Ances, B. (2011). Pathogenesis of HIV in the central nervous system. Curr. HIV/AIDS Rep. 8, 54-61. doi: 10.1007/s11904-010-0070-4
179. Valiunas, V., Polosina, Y. Y., Miller, H., Potapova, I. A., Valiuniene, L., Doronin, S., et al. (2005). Connexin-specific cell-to-cell transfer of short interfering RNA by gap junctions. J. Physiol. 568, 459-468. doi: 10.1113/jphysiol.2005.090985
180. Wallraff, A., Kohling, R., Heinemann, U., Theis, M., Willecke, K., and Steinhauser, C. (2006). The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus. J. Neurosci. 26, 5438-5447. doi: 10.1523/JNEUROSCI.0037-06.2006
181. Wallraff, A., Odermatt, B., Willecke, K., and Steinhauser, C. (2004). Distinct types of astroglial cells in the hippocampus differ in gap junction coupling. Glia 48, 36-43. doi: 10.1002/glia.20040
182. Walz, W., and Hertz, L. (1983). Functional interactions between neurons and astrocytes. II. Potassium homeostasis at the cellular level. Prog. Neurobiol. 20, 133-183. doi: 10.1016/0301-0082(83)90013-8
183. Wang, J., Ma, M., Locovei, S., Keane, R. W., and Dahl, G. (2007). Modulation of membrane channel currents by gap junction protein mimetic peptides: size matters. Am. J. Physiol. Cell Physiol. 293, C1112-C1119. doi: 10.1152/ajpcell.00097.2007
184. Wasseff, S. K., and Scherer, S. S. (2014). Activated microglia do not form functional gap junctions in vivo. J. Neuroimmunol. 269, 90-93. doi: 10.1016/j.jneuroim.2014.02.005
185. Willecke, K., Eiberger, J., Degen, J., Eckardt, D., Romualdi, A., Guldenagel, M., et al. (2002). Structural and functional diversity of connexin genes in the mouse and human genome. Biol. Chem. 383, 725-737. doi: 10.1515/BC.2002.076
186. Wong, R. O., Chernjavsky, A., Smith, S. J., and Shatz, C. J. (1995). Early functional neural networks in the developing retina. Nature 374, 716-718. doi: 10.1038/374716a0
187. Wu, D. C., Jackson-Lewis, V., Vila, M., Tieu, K., Teismann, P., Vadseth, C., et al. (2002). Blockade of microglial activation is neuroprotective in the 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J. Neurosci. 22, 1763-1771.
188. Wu, Z., Tokuda, Y., Zhang, X. W., and Nakanishi, H. (2008). Age-dependent responses of glial cells and leptomeninges during systemic inflammation. Neurobiol. Dis. 32, 543-551. doi: 10.1016/j.nbd.2008.09.002
189. Xiong, J., and Kielian, T. (2013). Microglia in juvenile neuronal ceroid lipofuscinosis are primed toward a pro-inflammatory phenotype. J. Neurochem. 127, 245-258. doi: 10.1111/jnc.12385
190. Xu, Q., Cheong, Y. K., He, S. Q., Tiwari, V., Liu, J., Wang, Y., et al. (2014). Suppression of spinal connexin 43 expression attenuates mechanical hypersensitivity in rats after an L5 spinal nerve injury. Neurosci. Lett. 566, 194-199. doi: 10.1016/j.neulet.2014.03.004
191. Xu, X., Li, W. E., Huang, G. Y., Meyer, R., Chen, T., Luo, Y., et al. (2001). Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions. J. Cell Biol. 154, 217-230. doi: 10.1083/jcb.200105047
192. Yamanaka, K., Chun, S. J., Boillee, S., Fujimori-Tonou, N., Yamashita, H., Gutmann, D. H., et al. (2008). Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat. Neurosci. 11, 251-253. doi: 10.1038/nn2047
193. Yawata, I., Takeuchi, H., Doi, Y., Liang, J., Mizuno, T., and Suzumura, A. (2008). Macrophage-induced neurotoxicity is mediated by glutamate and attenuated by glutaminase inhibitors and gap junction inhibitors. Life Sci. 82, 1111-1116. doi: 10.1016/j.lfs.2008.03.010
194. Ye, Z. C., Wyeth, M. S., Baltan-Tekkok, S., and Ransom, B. R. (2003). Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J. Neurosci. 23, 3588-3596.
195. Yeager, M., and Harris, A. L. (2007). Gap junction channel structure in the early 21st century: facts and fantasies. Curr. Opin. Cell Biol. 19, 521-528. doi: 10.1016/j.ceb.2007.09.001
196. Yrjanheikki, J., Keinanen, R., Pellikka, M., Hokfelt, T., and Koistinaho, J. (1998). Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc. Natl. Acad. Sci. U.S.A. 95, 15769-15774. doi: 10.1073/pnas.95.26.15769
197. Yudkoff, M. (1997). Brain metabolism of branched-chain amino acids. Glia 21, 92-98. doi: 10.1002/(SICI)1098-1136(199709)21:1<92::AIDGLIA10>3.0.CO;2-W
198. Zhu, S., Stavrovskaya, I. G., Drozda, M., Kim, B. Y., Ona, V., Li, M., et al. (2002). Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417, 74-78. doi: 10.1038/417074a
199. Zietlow, R., Dunnett, S. B., and Fawcett, J. W. (1999). The effect of microglia on embryonic dopaminergic neuronal survival in vitro: diffusible signals from neurons and glia change microglia from neurotoxic to neuroprotective. Eur. J. Neurosci. 11, 1657-1667. doi: 10.1046/j.1460-9568.1999.00583.x
200. Ziv, Y., Avidan, H., Pluchino, S., Martino, G., and Schwartz, M. (2006a). Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proc. Natl. Acad. Sci. U.S.A. 103, 13174-13179. doi: 10.1073/pnas.0603747103
201. Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Greenberg, N., et al. (2006b). Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9, 268-275. doi: 10.1038/nn1629
202. Zlomuzica, A., Reichinnek, S., Maxeiner, S., Both, M., May, E., Worsdorfer, P., et al. (2010). Deletion of connexin45 in mouse neurons disrupts one-trial object recognition and alters kainate-induced gamma-oscillations in the hippocampus. Physiol. Behav. 101, 245-253. doi: 10.1016/j.physbeh.2010.05.007