Psychopharmacology

, Volume 235, Issue 1, pp 1–12 | Cite as

Gap junction channels as potential targets for the treatment of major depressive disorder

  • Qian Ren
  • Zhen-Zhen Wang
  • Shi-Feng Chu
  • Cong-Yuan Xia
  • Nai-Hong Chen
Review
  • 402 Downloads

Abstract

Background

Major depressive disorder (MDD) remains a major public health problem worldwide. The association between MDD and the dysfunction of gap junction channels (GJCs) in glial cells, especially astrocytes, is still controversial.

Objective

This review provides an overview of the role of astrocyte GJCs in LMDD.

Results

Exposure to chronic unpredictable stress caused a reduction in connexin expression in the rat prefrontal cortex, a result that is consistent with clinical findings reported in postmortem studies of brains from MDD patients. Chronic antidepressant treatment in these rats increased the expression of connexins. However, pharmacological GJC blockade in normal rodents decreased connexin expression and caused depressive-like behaviors. Furthermore, GJC dysfunction affects electrical conductance, metabolic coupling and secondary messengers, and inflammatory responses, which are consistent with current hypotheses on MDD. All these results provide a comprehensive overview of the neurobiology of MDD.

Conclusion

This review supports the hypothesis that the regulation of GJCs between astrocytes could be an underlying mechanism for the therapeutic effect of antidepressants.

Keywords

Major depressive disorder Gap junction channels Connexin 43 Antidepressants Connexin 43 blockers 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81573636, U1402221, 81560663), PUMC Youth Fund (3332016058), the Fundamental Research Funds for the Central Universities (2014RC03, 2016RC350002), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-004), the Scientific Research Foundation of the Higher Education Institutions of Human Province (15K091), and Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (BZ0150).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. Abudara V, Roux L, Dallerac G, Matias I, Dulong J, Mothet JP, Rouach N, Giaume C (2015) Activated microglia impairs neuroglial interaction by opening Cx43 hemichannels in hippocampal astrocytes. Glia63: 795–811Google Scholar
  2. Albrecht J, Rafalowska U (1987) Enhanced potassium-stimulated gamma-aminobutyric acid release by astrocytes derived from rats with early hepatogenic encephalopathy. J Neurochem 49:9–11PubMedGoogle Scholar
  3. Albrecht J, Simmons M, Dutton GR, Norenberg MD (1991) Aluminum chloride stimulates the release of endogenous glutamate, taurine and adenosine from cultured rat cortical astrocytes. Neurosci Lett 127:105–107PubMedGoogle Scholar
  4. Allaman I, Belanger M, Magistretti PJ (2011) Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci 34:76–87PubMedGoogle Scholar
  5. Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A (2014) Gliotransmitters travel in time and space. Neuron 81:728–739PubMedPubMedCentralGoogle Scholar
  6. Araya-Callis C, Hiemke C, AbumariaN FG (2012) Chronic psychosocial stress and citalopram modulate the expression of the glial proteins GFAP and NDRG2 in the hippocampus. Psychopharmacology 224:209–222PubMedPubMedCentralGoogle Scholar
  7. Bal-Price A, Brown GC (2001) Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci 21:6480–6491PubMedGoogle Scholar
  8. Banasr M, Chowdhury GM, Terwilliger R, Newton SS, Duman RS, Behar KL, Sanacora G (2010) Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol Psychiatry 15:501–511PubMedGoogle Scholar
  9. Bao L, Locovei S, Dahl G (2004) Pannexin membrane channels are mechanosensitive conduits for ATP. FEBS Lett 572:65–68PubMedGoogle Scholar
  10. Batra N, Kar R, Jiang JX (2012) Gap junctions and hemichannels in signal transmission, function and development of bone. Biochim Biophys Acta 1818:1909–1918PubMedGoogle Scholar
  11. Bazzigaluppi P, Weisspapir I, Stefanovic B, Leybaert L, Carlen PL (2017) Astrocytic gap junction blockade markedly increases extracellular potassium without causing seizures in the mouse neocortex. Neurobiol Dis 101:1–7PubMedGoogle Scholar
  12. Belousov AB, Fontes JD, Freitas-Andrade M, Naus CC (2017) Gap junctions and hemichannels: communicating cell death in neurodevelopment and disease. BMC Cell Biol 18:4PubMedPubMedCentralGoogle Scholar
  13. Bennett MV, Garre JM, Orellana JA, Bukauskas FF, Nedergaard M, Saez JC (2012) Connexin and pannexin hemichannels in inflammatory responses of glia and neurons. Brain Res 1487:3–15PubMedPubMedCentralGoogle Scholar
  14. Bernard R, Kerman IA, Thompson RC, Jones EG, Bunney WE, Barchas JD, Schatzberg AF, Myers RM, Akil H, Watson SJ (2011) Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol Psychiatry 16:634–646PubMedGoogle Scholar
  15. Blomstrand F, Aberg ND, Eriksson PS, Hansson E, Ronnback L (1999) Extent of intercellular calcium wave propagation is related to gap junction permeability and level of connexin-43 expression in astrocytes in primary cultures from four brain regions. Neuroscience 92:255–265PubMedGoogle Scholar
  16. Boitano S, Dirksen ER, Sanderson MJ (1992) Intercellular propagation of calcium waves mediated by inositol trisphosphate. Science 258:292–295PubMedGoogle Scholar
  17. Bolanos JP, Almeida A, Fernandez E, Medina JM, Land JM, Clark JB, Heales SJ (1997) Potential mechanisms for nitric oxide-mediated impairment of brain mitochondrial energy metabolism. Biochem Soc Trans 25:944–949PubMedGoogle Scholar
  18. Bolanos JP, Medina JM (1996) Induction of nitric oxide synthase inhibits gap junction permeability in cultured rat astrocytes. J Neurochem 66:2091–2099PubMedGoogle Scholar
  19. Bowley MP, Drevets WC, Ongur D, Price JL (2002) Low glial numbers in the amygdala in major depressive disorder. Biol Psychiatry 52:404–412PubMedGoogle Scholar
  20. Bowser DN, Khakh BS (2007) Vesicular ATP is the predominant cause of intercellular calcium waves in astrocytes. J Gen Physiol 129:485–491PubMedPubMedCentralGoogle Scholar
  21. Calegari F, Coco S, Taverna E, Bassetti M, Verderio C, Corradi N, Matteoli M, Rosa P (1999) A regulated secretory pathway in cultured hippocampal astrocytes. J Biol Chem 274:22539–22547PubMedGoogle Scholar
  22. Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, Fang YY, Zhang J, Li SJ, Xiong WC, Yan HC, Gao YB, Liu JH, Li XW, Sun LR, Zeng YN, Zhu XH, Gao TM (2013) Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med19: 773–777Google Scholar
  23. Chana G, Landau S, Beasley C, Everall IP, Cotter D (2003) Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density. Biol Psychiatry 53:1086–1098PubMedGoogle Scholar
  24. Contreras JE, Sanchez HA, Eugenin EA, Speidel D, Theis M, Willecke K, Bukauskas FF, Bennett MV, Saez JC (2002) 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 U S A 99:495–500PubMedGoogle Scholar
  25. Cotrina ML, Lin JH, Alves-Rodrigues A, Liu S, Li J, Azmi-Ghadimi H, Kang J, Naus CC, Nedergaard M (1998) Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci U S A 95:15735–15740PubMedPubMedCentralGoogle Scholar
  26. Cotrina ML, Lin JH, Lopez-Garcia JC, Naus CC, Nedergaard M (2000) ATP-mediated glia signaling. J Neurosci 20:2835–2844PubMedGoogle Scholar
  27. Cotrina ML, Nedergaard M (2012) Brain connexins in demyelinating diseases: therapeutic potential of glial targets. Brain Res 1487:61–68PubMedPubMedCentralGoogle Scholar
  28. Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP (2002) Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex 12:386–394PubMedGoogle Scholar
  29. Cotter D, Mackay D, Landau S, Kerwin R, Everall I (2001) Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry 58:545–553PubMedGoogle Scholar
  30. Cronin M, Anderson PN, Cook JE, Green CR, Becker DL (2008) Blocking connexin43 expression reduces inflammation and improves functional recovery after spinal cord injury. Mol Cell Neurosci 39:152–160PubMedGoogle Scholar
  31. Czeh B, Simon M, Schmelting B, Hiemke C, Fuchs E (2006) Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology 31:1616–1626PubMedGoogle Scholar
  32. D'Hondt C, Iyyathurai J, Vinken M, Rogiers V, Leybaert L, Himpens B, Bultynck G (2013) Regulation of connexin- and pannexin-based channels by post-translational modifications. Biol Cell 105:373–398PubMedGoogle Scholar
  33. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105PubMedGoogle Scholar
  34. Davidson JO, Drury PP, Green CR, Nicholson LF, Bennet L, Gunn AJ (2014) Connexin hemichannel blockade is neuroprotective after asphyxia in preterm fetal sheep. PLoS One 9:e96558PubMedPubMedCentralGoogle Scholar
  35. Davidson JO, Green CR, Bennet L, Gunn AJ (2015) Battle of the hemichannels—connexins and pannexins in ischemic brain injury. Int J Dev Neurosci 45:66–74PubMedGoogle Scholar
  36. Davidson JO, Green CR, Bennet L, Nicholson LF, Danesh-Meyer H, O'Carroll SJ, Gunn AJ (2013) A key role for connexin hemichannels in spreading ischemic brain injury. Curr Drug Targets 14:36–46PubMedGoogle Scholar
  37. Davidson JO, Green CR, Nicholson LF, O'Carroll SJ, Fraser M, Bennet L, Gunn AJ (2012) Connexin hemichannel blockade improves outcomes in a model of fetal ischemia. Ann Neurol 71:121–132PubMedGoogle Scholar
  38. De Bock M, Decrock E, Wang N, Bol M, Vinken M, Bultynck G, Leybaert L (2014) The dual face of connexin-based astroglial Ca(2+) communication: a key player in brain physiology and a prime target in pathology. Biochim Biophys Acta 1843:2211–2232PubMedGoogle Scholar
  39. DeFlora A, Zocchi E, Guida L, Franco L, Bruzzone S (2004) Autocrine and paracrine calcium signaling by the CD38/NAD+/cyclic ADP-ribose system. Ann N Y Acad Sci 1028:176–191Google Scholar
  40. Diezmos EF, Bertrand PP, Liu L (2016) Purinergic signaling in gut inflammation: the role of connexins and pannexins. Front Neurosci 10:311PubMedPubMedCentralGoogle Scholar
  41. Ducrocq F, Vaiva G, Cottencin O, Molenda S, Bailly D (2001) Post-traumatic stress, post-traumatic depression and major depressive episode: literature. Encéphale 27:159–168PubMedGoogle Scholar
  42. Duffy HS, John GR, Lee SC, Brosnan CF, Spray DC (2000) Reciprocal regulation of the junctional proteins claudin-1 and connexin43 by interleukin-1beta in primary human fetal astrocytes. J Neurosci 20: Rc114Google Scholar
  43. Dunina-Barkovskaya A (1998) pH dependence of junctional conductance. MembrCell Biol 11:793–801Google Scholar
  44. Ezan P, Andre P, Cisternino S, Saubamea B, Boulay AC, Doutremer S, Thomas MA, Quenech'du N, Giaume C, Cohen-Salmon M (2012) Deletion of astroglial connexins weakens the blood-brain barrier. J Cereb Blood Flow Metab 32:1457–1467PubMedPubMedCentralGoogle Scholar
  45. Fatemi SH, Folsom TD, Reutiman TJ, Pandian T, Braun NN, Haug K (2008) Chronic psychotropic drug treatment causes differential expression of connexin 43 and GFAP in frontal cortex of rats. Schizophr Res 104:127–134PubMedGoogle Scholar
  46. Figiel M, Allritz C, Lehmann C, Engele J (2007) Gap junctional control of glial glutamate transporter expression. Mol Cell Neurosci 35:130–137PubMedGoogle Scholar
  47. Fiori MC, Reuss L, Cuello LG, Altenberg GA (2014) Functional analysis and regulation of purified connexin hemichannels. Front Physiol 5:71PubMedPubMedCentralGoogle Scholar
  48. Fogal B, Li J, Lobner D, McCullough LD, Hewett SJ (2007) System x(c)- activity and astrocytes are necessary for interleukin-1 beta-mediated hypoxic neuronal injury. J Neurosci 27:10094–10105PubMedGoogle Scholar
  49. Fonseca L, Mayer L, Orange D, Driscoll N (2002) The high-frequency backscattering angular response of gassy sediments: model/data comparison from the Eel River Margin, California. J Acoust Soc Am 111:2621–2631PubMedGoogle Scholar
  50. Freitas-Andrade M, Naus CC (2016) Astrocytes in neuroprotection and neurodegeneration: the role of connexin43 and pannexin1. Neuroscience 323:207–221PubMedGoogle Scholar
  51. Froger N, Orellana JA, Calvo CF, Amigou E, Kozoriz MG, Naus CC, Saez JC, Giaume C (2010) Inhibition of cytokine-induced connexin43 hemichannel activity in astrocytes is neuroprotective. Mol Cell Neurosci 45:37–46PubMedGoogle Scholar
  52. Giaume C, Cordier J, Glowinski J (1992) Endothelins inhibit junctional permeability in cultured mouse astrocytes. EurJ Neurosci 4:877–881Google Scholar
  53. Giaume C, Tabernero A, Medina JM (1997) Metabolic trafficking through astrocytic gap junctions. Glia21: 114–123Google Scholar
  54. Giaume C, Venance L (1998) Intercellularcalcium signaling and gap junctional communication in astrocytes. Glia24: 50–64Google Scholar
  55. Gibbons HM, Dragunow M (2006) Microglia induce neural cell death via a proximity-dependent mechanism involving nitric oxide. Brain Res 1084:1–15PubMedGoogle Scholar
  56. Giepmans BN (2004) Gap junctions and connexin-interacting proteins. Cardiovasc Res 62:233–245PubMedGoogle Scholar
  57. Gittins RA, Harrison PJ (2011) A morphometric study of glia and neurons in the anterior cingulate cortex in mood disorder. J Affect Disord 133:328–332PubMedGoogle Scholar
  58. Godsil BP, Kiss JP, Spedding M, Jay TM (2013) The hippocampal-prefrontal pathway: the weak link in psychiatric disorders? EurNeuropsychopharmacol 23:1165–1181Google Scholar
  59. Grippo AJ, Moffitt JA, Henry MK, Firkins R, Senkler J, McNeal N, Wardwell J, Scotti MA, Dotson A, Schultz R (2015) Altered Connexin 43 and Connexin 45 protein expression in the heart as a function of social and environmental stress in the prairie vole. Stress 18:107–114PubMedGoogle Scholar
  60. Guthrie PB, Knappenberger J, Segal M, Bennett MV, Charles AC, Kater SB (1999) ATP released from astrocytes mediates glial calcium waves. J Neurosci 19:520–528PubMedGoogle Scholar
  61. Halassa MM, Haydon PG (2010) Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annu Rev Physiol 72:335–355PubMedPubMedCentralGoogle Scholar
  62. Hassinger TD, Guthrie PB, Atkinson PB, Bennett MV, Kater SB (1996) An extracellular signaling component in propagation of astrocytic calcium waves. Proc Natl Acad Sci U S A 93:13268–13273PubMedPubMedCentralGoogle Scholar
  63. Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86:1009–1031PubMedGoogle Scholar
  64. Heales SJ, Bolanos JP, Stewart VC, Brookes PS, Land JM, Clark JB (1999) Nitric oxide, mitochondria and neurological disease. Biochim Biophys Acta 1410:215–228PubMedGoogle Scholar
  65. Hewett SJ, Csernansky CA, Choi DW (1994) Selective potentiation of NMDA-induced neuronal injury following induction of astrocytic iNOS. Neuron 13:487–494PubMedGoogle Scholar
  66. Hisaoka K, Tsuchioka M, Yano R, Maeda N, Kajitani N, Morioka N, Nakata Y, Takebayashi M (2011) Tricyclic antidepressant amitriptyline activates fibroblast growth factor receptor signaling in glial cells: involvement in glial cell line-derived neurotrophic factor production. J Biol Chem 286:21118–21128PubMedPubMedCentralGoogle Scholar
  67. Ionescu DF, Papakostas GI (2017) Experimental medication treatment approaches for depression. TranslPsychiatry 7:e1068Google Scholar
  68. Iwata M, Shirayama Y, Ishida H, Hazama GI, Nakagome K (2011) Hippocampal astrocytes are necessary for antidepressant treatment of learned helplessness rats. Hippocampus 21:877–884PubMedGoogle Scholar
  69. Jeanson T, Pondaven A, Ezan P, Mouthon F, Charveriat M, Giaume C (2015) Antidepressants impact Connexin 43 channel functions in astrocytes. Front Cell Neurosci 9:495PubMedGoogle Scholar
  70. John GR, Scemes E, Suadicani SO, Liu JS, Charles PC, Lee SC, Spray DC, Brosnan CF (1999) IL-1beta differentially regulates calcium wave propagation between primary human fetal astrocytes via pathways involving P2 receptors and gap junction channels. Proc Natl Acad Sci U S A 96:11613–11618PubMedPubMedCentralGoogle Scholar
  71. Kajitani N, Hisaoka-Nakashima K, Morioka N, Okada-Tsuchioka M, Kaneko M, Kasai M, Shibasaki C, Nakata Y, Takebayashi M (2012) Antidepressant acts on astrocytes leading to an increase in the expression of neurotrophic/growth factors: differential regulation of FGF-2 by noradrenaline. PLoS One 7:e51197PubMedPubMedCentralGoogle Scholar
  72. Kawasaki A, Hayashi T, Nakachi K, Trosko JE, Sugihara K, Kotake Y, Ohta S (2009) Modulation of connexin43 in rotenone-induced model of Parkinson's disease. Neuroscience 160:61–68PubMedGoogle Scholar
  73. Khundakar A, Morris C, Oakley A, Thomas AJ (2011a) A morphometric examination of neuronal and glial cell pathology in the orbitofrontal cortex in late-life depression. Int Psychogeriatr 23:132–140PubMedGoogle Scholar
  74. Khundakar AA, Morris CM, Oakley AE, Thomas AJ (2011b) Cellular pathology within the anterior cingulate cortex of patients with late-life depression: a morphometric study. Psychiatry Res 194:184–189PubMedGoogle Scholar
  75. Klumpp L, Sezgin EC, Skardelly M, Eckert F, Huber SM (2017) KCa3.1 channels and glioblastoma: in vitro studies. Curr NeuropharmacolGoogle Scholar
  76. Kimelberg HK (2007) Supportive or information-processing functions of the mature protoplasmic astrocyte in the mammalian CNS? A critical appraisal. Neuron Glia Biol 3:181–189PubMedPubMedCentralGoogle Scholar
  77. Kinsner A, Pilotto V, Deininger S, Brown GC, Coecke S, Hartung T, Bal-Price A (2005) Inflammatory neurodegeneration induced by lipoteichoic acid from Staphylococcus aureus is mediated by glia activation, nitrosative and oxidative stress, and caspase activation. J Neurochem 95:1132–1143PubMedGoogle Scholar
  78. Kofuji P, Newman EA (2004) Potassium buffering in the central nervous system. Neuroscience 129:1045–1056PubMedPubMedCentralGoogle Scholar
  79. Koulakoff A, Mei X, Orellana JA, Saez JC, Giaume C (2012) Glial connexin expression and function in the context of Alzheimer's disease. Biochim Biophys Acta 1818:2048–2057PubMedGoogle Scholar
  80. Koyama Y, Ishibashi T, Okamoto T, Matsuda T, Hashimoto H, Baba A (2000) Transient treatments with L-glutamate and threo-beta-hydroxyaspartate induce swelling of rat cultured astrocytes. Neurochem Int 36:167–173PubMedGoogle Scholar
  81. Lucassen PJ, Pruessner J, Sousa N, Almeida OF, Van Dam AM, Rajkowska G, Swaab DF, Czeh B (2014) Neuropathology of stress. Acta Neuropathol 127:109–135PubMedGoogle Scholar
  82. Madelian V, Martin DL, Lepore R, Perrone M, Shain W (1985) Beta-receptor-stimulated and cyclic adenosine 3′,5′-monophosphate-mediated taurine release from LRM55 glial cells. J Neurosci 5:3154–3160PubMedGoogle Scholar
  83. Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, Kubera M, Bob P, Lerer B, Maj M (2009) The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 24:27–53PubMedGoogle Scholar
  84. Magarinos AM, McEwen BS (1995) Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: comparison of stressors. Neuroscience 69:83–88PubMedGoogle Scholar
  85. Magarinos AM, McEwen BS, Flugge G, Fuchs E (1996) Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci 16:3534–3540PubMedGoogle Scholar
  86. Makarenkova HP, Shestopalov VI (2014) The role of pannexin hemichannels in inflammation and regeneration. Front Physiol 5:63PubMedPubMedCentralGoogle Scholar
  87. Mallei A, Shi B, Mocchetti I (2002) Antidepressant treatments induce the expression of basic fibroblast growth factor in cortical and hippocampal neurons. Mol Pharmacol 61:1017–1024PubMedGoogle Scholar
  88. Martinez AD, Saez JC (1999) Arachidonic acid-induced dye uncoupling in rat cortical astrocytes is mediated by arachidonic acid byproducts. Brain Res 816:411–423PubMedGoogle Scholar
  89. McNaught KS, Jenner P (1999) Altered glial function causes neuronal death and increases neuronal susceptibility to 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced toxicity in astrocytic/ventral mesencephalic co-cultures. J Neurochem 73:2469–2476PubMedGoogle Scholar
  90. Meme W, Ezan P, Venance L, Glowinski J, Giaume C (2004) ATP-induced inhibition of gap junctional communication is enhanced by interleukin-1 beta treatment in cultured astrocytes. Neuroscience 126:95–104PubMedGoogle Scholar
  91. Metea MR, Newman EA (2006) Glial cells dilate and constrict blood vessels: a mechanism of neurovascular coupling. J Neurosci 26:2862–2870PubMedPubMedCentralGoogle Scholar
  92. Miguel-Hidalgo JJ, Wei J, Andrew M, Overholser JC, Jurjus G, Stockmeier CA, Rajkowska G (2002) Glia pathology in the prefrontal cortex in alcohol dependence with and without depressive symptoms. Biol Psychiatry 52:1121–1133PubMedPubMedCentralGoogle Scholar
  93. Miller RF (2004) D-serine as a glial modulator of nerve cells. Glia 47:275–283PubMedGoogle Scholar
  94. Morioka N, Suekama K, Zhang FF, Kajitani N, Hisaoka-Nakashima K, Takebayashi M, Nakata Y (2014) Amitriptyline up-regulates connexin43-gap junction in rat cultured cortical astrocytes via activation of the p38 and c-Fos/AP-1 signalling pathway. Br J Pharmacol 171:2854–2867PubMedPubMedCentralGoogle Scholar
  95. Morley GE, Taffet SM, Delmar M (1996) Intramolecular interactions mediate pH regulation of connexin43 channels. Biophys J 70:1294–1302PubMedPubMedCentralGoogle Scholar
  96. Mostafavi H, Khaksarian M, Joghataei MT, Hassanzadeh G, Soleimani M, Eftekhari S, Soleimani M, Mousavizadeh K, Hadjighassem MR (2014) Fluoxetin upregulates connexin 43 expression in astrocyte. Basic Clin Neurosci 5:74–79PubMedPubMedCentralGoogle Scholar
  97. Muller T, Moller T, Neuhaus J, Kettenmann H (1996) Electrical coupling among Bergmann glial cells and its modulation by glutamate receptor activation. Glia17: 274–284Google Scholar
  98. Munoz MF, Puebla M, Figueroa XF (2015) Control of the neurovascular coupling by nitric oxide-dependent regulation of astrocytic Ca(2+) signaling. Front Cell Neurosci 9:59PubMedPubMedCentralGoogle Scholar
  99. Murphy S, Pearce B (1988) Eicosanoids in the CNS: sources and effects. Prostaglandins Leukot Essent Fatty Acids 31:165–170PubMedGoogle Scholar
  100. Mylvaganam S, Ramani M, Krawczyk M, Carlen PL (2014) Roles of gap junctions, connexins, and pannexins in epilepsy. Front Physiol 5:172PubMedPubMedCentralGoogle Scholar
  101. Nakase T, Yoshida Y, Nagata K (2006) Enhanced connexin 43 immunoreactivity in penumbral areas in the human brain following ischemia. Glia54: 369–375Google Scholar
  102. Naus CC, Laird DW (2010) Implications and challenges of connexin connections to cancer. Nat Rev Cancer 10:435–441PubMedGoogle Scholar
  103. Nichols NR, Osterburg HH, Masters JN, Millar SL, Finch CE (1990) Messenger RNA for glial fibrillary acidic protein is decreased in rat brain following acute and chronic corticosterone treatment. Brain Res Mol Brain Res 7:1–7PubMedGoogle Scholar
  104. Ongur D, Drevets WC, Price JL (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A 95:13290–13295PubMedPubMedCentralGoogle Scholar
  105. Orellana JA, Avendano BC, Montero TD (2014) Role of connexins and pannexins in ischemic stroke. CurrMedChem 21:2165–2182Google Scholar
  106. Orellana JA, Saez PJ, Shoji KF, Schalper KA, Palacios-Prado N, Velarde V, Giaume C, Bennett MV, Saez JC (2009) Modulation of brain hemichannels and gap junction channels by pro-inflammatory agents and their possible role in neurodegeneration. Antioxid Redox Signal 11:369–399PubMedPubMedCentralGoogle Scholar
  107. Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, Mohr DC, Schatzberg AF (2016) Major depressive disorder. Nat Rev Dis Primers 2:16065PubMedGoogle Scholar
  108. Panatier A, Theodosis DT, Mothet JP, Touquet B, Pollegioni L, Poulain DA, Oliet SH (2006) Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 125:775–784PubMedGoogle Scholar
  109. Pannasch U, Rouach N (2013) Emerging role for astroglial networks in information processing: from synapse to behavior. Trends Neurosci 36:405–417PubMedGoogle Scholar
  110. Pannasch U, Vargova L, Reingruber J, Ezan P, Holcman D, Giaume C, Sykova E, Rouach N (2011) Astroglial networks scale synaptic activity and plasticity. Proc Natl Acad Sci U S A 108:8467–8472PubMedPubMedCentralGoogle Scholar
  111. Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (1994) Glutamate-mediated astrocyte-neuron signalling. Nature 369:744–747PubMedGoogle Scholar
  112. Patel D, Zhang X, Veenstra RD (2014) Connexin hemichannel and pannexin channel electrophysiology: how do they differ? FEBS Lett 588:1372–1378PubMedPubMedCentralGoogle Scholar
  113. Perea G, Navarrete M, Araque A (2009) Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32:421–431PubMedGoogle Scholar
  114. Plotkin LI (2014) Connexin 43 hemichannels and intracellular signaling in bone cells. Front Physiol 5:131PubMedPubMedCentralGoogle Scholar
  115. Quaegebeur A, Lange C, Carmeliet P (2011) The neurovascular link in health and disease: molecular mechanisms and therapeutic implications. Neuron 71:406–424PubMedGoogle Scholar
  116. Quesseveur G, Portal B, Basile JA, Ezan P, Mathou A, Halley H, Leloup C, Fioramonti X, Deglon N, Giaume C, Rampon C, Guiard BP (2015) Attenuated levels of hippocampal Connexin 43 and its phosphorylation correlate with antidepressant- and anxiolytic-like activities in mice. Front Cell Neurosci 9:490PubMedPubMedCentralGoogle Scholar
  117. Rajkowska G (2000) Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biol Psychiatry 48:766–777PubMedGoogle Scholar
  118. Rajkowska G, Miguel-Hidalgo JJ (2007) Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets 6:219–233PubMedPubMedCentralGoogle Scholar
  119. Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, Overholser JC, Roth BL, Stockmeier CA (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085–1098PubMedGoogle Scholar
  120. Rajkowska G, Selemon LD, Goldman-Rakic PS (1998) Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Arch Gen Psychiatry 55:215–224PubMedGoogle Scholar
  121. Rana S, Dringen R (2007) Gap junction hemichannel-mediated release of glutathione from cultured rat astrocytes. Neurosci Lett 415:45–48PubMedGoogle Scholar
  122. Retamal MA, Schalper KA, Shoji KF, Bennett MV, Saez JC (2007) Opening of connexin 43 hemichannels is increased by lowering intracellular redox potential. Proc Natl Acad Sci U S A 104:8322–8327PubMedPubMedCentralGoogle Scholar
  123. Reuss B, Dermietzel R, Unsicker K (1998) Fibroblast growth factor 2 (FGF-2) differentially regulates connexin (cx) 43 expression and function in astroglial cells from distinct brain regions. Glia22: 19–30Google Scholar
  124. Rossi D, Brambilla L, Valori CF, Crugnola A, Giaccone G, Capobianco R, Mangieri M, Kingston AE, Bloc A, Bezzi P, Volterra A (2005) Defective tumor necrosis factor-alpha-dependent control of astrocyte glutamate release in a transgenic mouse model of Alzheimer disease. J Biol Chem 280:42088–42096PubMedGoogle Scholar
  125. Rouach N, AvignoneE MW, Koulakoff A, Venance L, Blomstrand F, Giaume C (2002a) Gap junctions and connexin expression in the normal and pathological central nervous system. Biol Cell 94:457–475PubMedGoogle Scholar
  126. Rouach N, Tence M, Glowinski J, Giaume C (2002b) Costimulation of N-methyl-D-aspartate and muscarinic neuronal receptors modulates gap junctional communication in striatal astrocytes. Proc Natl Acad Sci U S A 99:1023–1028PubMedPubMedCentralGoogle Scholar
  127. Sapolsky RM (1996) Stress, glucocorticoids, and damage to the nervous system: the current state of confusion. Stress 1:1–19PubMedGoogle Scholar
  128. Schell MJ, Molliver ME, Snyder SH (1995) D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci U S A 92:3948–3952PubMedPubMedCentralGoogle Scholar
  129. Selemon LD, Rajkowska G, Goldman-Rakic PS (1998) Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional, stereologic counting method. J Comp Neurol 392:402–412PubMedGoogle Scholar
  130. Simard M, Nedergaard M (2004) The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129:877–896PubMedGoogle Scholar
  131. Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY, Uylings HB, Friedman L, Rajkowska G (2004) Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry 56:640–650PubMedPubMedCentralGoogle Scholar
  132. Stout CE, Costantin JL, Naus CC, Charles AC (2002) Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J Biol Chem 277:10482–10488PubMedGoogle Scholar
  133. Sun JD, Liu Y, Yuan YH, Li J, Chen NH (2012) Gap junction dysfunction in the prefrontal cortex induces depressive-like behaviors in rats. Neuropsychopharmacology 37:1305–1320PubMedGoogle Scholar
  134. Swaab DF, Bao AM, Lucassen PJ (2005) The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 4:141–194PubMedGoogle Scholar
  135. Takeuchi H, Suzumura A (2014) Gap junctions and hemichannels composed of connexins: potential therapeutic targets for neurodegenerative diseases. Front Cell Neurosci 8:189PubMedPubMedCentralGoogle Scholar
  136. Thornton P, Pinteaux E, Gibson RM, Allan SM, Rothwell NJ (2006) Interleukin-1-induced neurotoxicity is mediated by glia and requires caspase activation and free radical release. J Neurochem 98:258–266PubMedGoogle Scholar
  137. Vargas AA, Cisterna BA, Saavedra-Leiva F, Urrutia C, Cea LA, Vielma AH, Gutierrez-Maldonado SE, Martin AJ, Pareja-Barrueto C, Escalona Y, Schmachtenberg O, Lagos CF, Perez-Acle T, Saez JC (2017) On biophysical properties and sensitivity to gap junction blockers of Connexin 39 hemichannels expressed in HeLa cells. Front Physiol 8:38PubMedPubMedCentralGoogle Scholar
  138. Vergara L, Bao X, Bello-Reuss E, Reuss L (2003) Do connexin 43 gap-junctional hemichannels activate and cause cell damage during ATP depletion of renal-tubule cells? Acta Physiol Scand 179:33–38PubMedGoogle Scholar
  139. Vis JC, Nicholson LF, Faull RL, Evans WH, Severs NJ, Green CR (1998) Connexin expression in Huntington's diseased human brain. Cell Biol Int 22:837–847PubMedGoogle Scholar
  140. Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6:626–640PubMedGoogle Scholar
  141. Wang N, De Bock M, Decrock E, Bol M, Gadicherla A, Vinken M, Rogiers V, Bukauskas FF, Bultynck G, Leybaert L (2013) Paracrine signaling through plasma membrane hemichannels. Biochim Biophys Acta 1828:35–50PubMedGoogle Scholar
  142. Wentlandt K, Kushnir M, Naus CC, Carlen PL (2004) Ethanol inhibits gap-junctional coupling between P19 cells. Alcohol Clin Exp Res 28:1284–1290PubMedGoogle Scholar
  143. Xia CY, Chu SF, Zhang S, Gao Y, Ren Q, Lou YX, Luo P, Tian MT, Wang ZQ, Du GH, Tomioka Y, Yamakuni T, Zhang Y, Wang ZZ, Chen NH (2017) Ginsenoside Rg1 alleviates corticosterone-induced dysfunction of gap junctions in astrocytes. J Ethnopharmacol 208:207–213PubMedGoogle Scholar
  144. Xu HL, Pelligrino DA (2007) ATP release and hydrolysis contribute to rat pial arteriolar dilatation elicited by neuronal activation. ExpPhysiol 92:647–651Google Scholar
  145. Zhang H, Zhao Y, Wang Z (2015) Chronic corticosterone exposure reduces hippocampal astrocyte structural plasticity and induces hippocampal atrophy in mice. Neurosci Lett 592:76–81PubMedGoogle Scholar
  146. Zhou F, Yao HH, Wu JY, Yang YJ, Ding JH, Zhang J, Hu G (2006) Activation of group II/III metabotropic glutamate receptors attenuates LPS-induced astroglial neurotoxicity via promoting glutamate uptake. J Neurosci Res 84:268–277PubMedGoogle Scholar
  147. Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6:43–50PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Qian Ren
    • 1
  • Zhen-Zhen Wang
    • 1
  • Shi-Feng Chu
    • 1
  • Cong-Yuan Xia
    • 1
  • Nai-Hong Chen
    • 1
    • 2
  1. 1.State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
  2. 2.College of PharmacyHunan University of Chinese MedicineChangshaChina

Personalised recommendations