Gap junction channels as potential targets for the treatment of major depressive disorder
- 419 Downloads
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.
This review provides an overview of the role of astrocyte GJCs in LMDD.
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.
This review supports the hypothesis that the regulation of GJCs between astrocytes could be an underlying mechanism for the therapeutic effect of antidepressants.
KeywordsMajor depressive disorder Gap junction channels Connexin 43 Antidepressants Connexin 43 blockers
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.
- 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
- 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
- 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
- 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
- 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
- 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
- Dunina-Barkovskaya A (1998) pH dependence of junctional conductance. MembrCell Biol 11:793–801Google Scholar
- Giaume C, Cordier J, Glowinski J (1992) Endothelins inhibit junctional permeability in cultured mouse astrocytes. EurJ Neurosci 4:877–881Google Scholar
- Giaume C, Tabernero A, Medina JM (1997) Metabolic trafficking through astrocytic gap junctions. Glia21: 114–123Google Scholar
- Giaume C, Venance L (1998) Intercellularcalcium signaling and gap junctional communication in astrocytes. Glia24: 50–64Google Scholar
- Godsil BP, Kiss JP, Spedding M, Jay TM (2013) The hippocampal-prefrontal pathway: the weak link in psychiatric disorders? EurNeuropsychopharmacol 23:1165–1181Google Scholar
- 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
- Ionescu DF, Papakostas GI (2017) Experimental medication treatment approaches for depression. TranslPsychiatry 7:e1068Google Scholar
- 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
- 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
- Klumpp L, Sezgin EC, Skardelly M, Eckert F, Huber SM (2017) KCa3.1 channels and glioblastoma: in vitro studies. Curr NeuropharmacolGoogle Scholar
- 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
- 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
- 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
- Nakase T, Yoshida Y, Nagata K (2006) Enhanced connexin 43 immunoreactivity in penumbral areas in the human brain following ischemia. Glia54: 369–375Google Scholar
- Orellana JA, Avendano BC, Montero TD (2014) Role of connexins and pannexins in ischemic stroke. CurrMedChem 21:2165–2182Google Scholar
- 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
- 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
- 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
- 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
- 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
- Xu HL, Pelligrino DA (2007) ATP release and hydrolysis contribute to rat pial arteriolar dilatation elicited by neuronal activation. ExpPhysiol 92:647–651Google Scholar