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Neuronal gap junction coupling as the primary determinant of the extent of glutamate-mediated excitotoxicity

  • Translational Neurosciences - Review article
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Abstract

In the mammalian central nervous system (CNS), coupling of neurons by gap junctions (electrical synapses) increases during early postnatal development, then decreases, but increases in the mature CNS following neuronal injury, such as ischemia, traumatic brain injury and epilepsy. Glutamate-dependent neuronal death also occurs in the CNS during development and neuronal injury, i.e., at the time when neuronal gap junction coupling is increased. Here, we review our recent studies on regulation of neuronal gap junction coupling by glutamate in developing and injured neurons and on the role of gap junctions in neuronal cell death. A modified model of the mechanisms of glutamate-dependent neuronal death is discussed, which includes neuronal gap junction coupling as a critical part of these mechanisms.

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References

  • Adams SM, de Rivero Vaccari JC, Corriveau RA (2004) Pronounced cell death in the absence of NMDA receptors in the developing somatosensory thalamus. J Neurosci 24:9441–9450

    Article  CAS  PubMed  Google Scholar 

  • Arumugam H, Liu X, Colombo PJ, Corriveau RA, Belousov AB (2005) NMDA receptors regulate developmental gap junction uncoupling via CREB signaling. Nat Neurosci 8:1720–1726

    Article  CAS  PubMed  Google Scholar 

  • Arundine M, Tymianski M (2004) Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell Mol Life Sci 61:657–668

    Article  CAS  PubMed  Google Scholar 

  • Bargiotas P, Krenz A, Hormuzdi SG, Ridder DA, Herb A, Barakat W, Penuela S, von Engelhardt J, Monyer H, Schwaninger M (2011) Pannexins in ischemia-induced neurodegeneration. Proc Natl Acad Sci USA 108:20772–20777

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Belluardo N, Mudo G, Trovato-Salinaro A, Le Gurun S, Charollais A, Serre-Beinier V, Amato G, Haefliger JA, Meda P, Condorelli DF (2000) Expression of connexin36 in the adult and developing rat brain. Brain Res 865:121–138

    Article  CAS  PubMed  Google Scholar 

  • Belousov AB (2012) Novel model for the mechanisms of glutamate-dependent excitotoxicity: role of neuronal gap junctions. Brain Res 1487:123–130

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Belousov AB, Fontes JD (2013) Neuronal gap junctions: making and breaking connections during development and injury. Trends Neurosci 36:227–236

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Belousov AB, O’Hara BF, Denisova JV (2001) Acetylcholine becomes the major excitatory neurotransmitter in the hypothalamus in vitro in the absence of glutamate excitation. J Neurosci 21:2015–2027

    CAS  PubMed  Google Scholar 

  • Belousov AB, Wang Y, Song J-H, Denisova JV, Berman NE, Fontes JD (2012) Neuronal gap junctions play a role in the secondary neuronal death following controlled cortical impact. Neurosci Lett 524:16–19

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ben-Ari Y (2001) Developing networks play a similar melody. Trends Neurosci 24:353–360

    Article  CAS  PubMed  Google Scholar 

  • Bennett MV, Zukin RS (2004) Electrical coupling and neuronal synchronization in the mammalian brain. Neuron 41:495–511

    Article  CAS  PubMed  Google Scholar 

  • Beraudi A, Bruno V, Battaglia G, Biagioni F, Rampello L, Nicoletti F, Poli A (2007) Pharmacological activation of mGlu2/3 metabotropic glutamate receptors protects retinal neurons against anoxic damage in the goldfish Carassius auratus. Exp Eye Res 84:544–552

    Article  CAS  PubMed  Google Scholar 

  • Beyer EC, Berthoud VM (2009) Chapter 1: The family of connexin genes. In: Locke D, Harris A (eds) A guide: Connexins. Humana Press, New York, pp 3–26

  • Chang Q, Pereda A, Pinter MJ, Balice-Gordon RJ (2000) Nerve injury induces gap junctional coupling among axotomized adult motor neurons. J Neurosci 20:674–684

    CAS  PubMed  Google Scholar 

  • Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634

    Article  CAS  PubMed  Google Scholar 

  • Cina C, Bechberger JF, Ozog MA, Naus CC (2007) Expression of connexins in embryonic mouse neocortical development. J Comp Neurol 504:298–313

    Article  CAS  PubMed  Google Scholar 

  • Condorelli DF, Trovato-Salinaro A, Mudo G, Mirone MB, Belluardo N (2003) Cellular expression of connexins in the rat brain: neuronal localization, effects of kainate-induced seizures and expression in apoptotic neuronal cells. Eur J Neurosci 18:1807–1827

    Article  PubMed  Google Scholar 

  • Connors BW, Long MA (2004) Electrical synapses in the mammalian brain. Annu Rev Neurosci 27:393–418

    Article  CAS  PubMed  Google Scholar 

  • Cusato K, Ripps H, Zakevicius J, Spray DC (2006) Gap junctions remain open during cytochrome c-induced cell death: relationship of conductance to ‘bystander’ cell killing. Cell Death Differ 13:1707–1714

    Article  CAS  PubMed  Google Scholar 

  • Davidson JO, Green CR, Nicholson LF, O’Carroll SJ, Fraser M, Bennet L, Jan Gunn A (2012) Connexin hemichannel blockade improves outcomes in a model of fetal ischemia. Ann Neurol 71:121–132

    Article  CAS  PubMed  Google Scholar 

  • De Cristobal J, Moro MA, Davalos A, Castillo J, Leza JC, Camarero J, Colado MI, Lorenzo P, Lizasoain I (2001) Neuroprotective effect of aspirin by inhibition of glutamate release after permanent focal cerebral ischaemia in rats. J Neurochem 79:456–459

    Article  PubMed  Google Scholar 

  • de Pina-Benabou MH, Szostak V, Kyrozis A, Rempe D, Uziel D, Urban-Maldonado M, Benabou S, Spray DC, Federoff HJ, Stanton PK, Rozental R (2005) Blockade of gap junctions in vivo provides neuroprotection after perinatal global ischemia. Stroke 36:2232–2237

    Article  PubMed  Google Scholar 

  • de Rivero Vaccari JC, Corriveau RA, Belousov AB (2007) Gap junctions are required for NMDA receptor-dependent cell death in developing neurons. J Neurophysiol 98:2878–2886

    Article  PubMed  Google Scholar 

  • 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, Sohl G, Gueldenagel M, Willecke K, Yarom Y (2003) 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 23:4700–4711

    PubMed  Google Scholar 

  • Deans MR, Gibson JR, Sellitto C, Connors BW, Paul DL (2001) Synchronous activity of inhibitory networks in neocortex requires electrical synapses containing connexin36. Neuron 31:477–485

    Article  CAS  PubMed  Google Scholar 

  • Decrock E, Vinken M, De Vuyst E, Krysko DV, D’Herde K, Vanhaecke T, Vandenabeele P, Rogiers V, Leybaert L (2009) Connexin-related signaling in cell death: to live or let die? Cell Death Differ 16:524–536

    Article  CAS  PubMed  Google Scholar 

  • Decrock E, De Bock M, Wang N, Gadicherla AK, Bol M, Delvaeye T, Vandenabeele P, Vinken M, Bultynck G, Krysko DV, Leybaert L (2013) IP3, a small molecule with a powerful message. Biochim Biophys Acta 1833:1772–1786

    Article  CAS  PubMed  Google Scholar 

  • Dupont E, Hanganu IL, Kilb W, Hirsch S, Luhmann HJ (2006) Rapid developmental switch in the mechanisms driving early cortical columnar networks. Nature 439:79–83

    Article  CAS  PubMed  Google Scholar 

  • Elias LA, Wang DD, Kriegstein AR (2007) Gap junction adhesion is necessary for radial migration in the neocortex. Nature 448:901–907

    Article  CAS  PubMed  Google Scholar 

  • Frantseva MV, Kokarovtseva L, Naus CG, Carlen PL, MacFabe D, Perez Velazquez JL (2002) Specific gap junctions enhance the neuronal vulnerability to brain traumatic injury. J Neurosci 22:644–653

    CAS  PubMed  Google Scholar 

  • Gajda Z, Gyengesi E, Hermesz E, Ali KS, Szente M (2003) Involvement of gap junctions in the manifestation and control of the duration of seizures in rats in vivo. Epilepsia 44:1596–1600

    Article  CAS  PubMed  Google Scholar 

  • Galarreta M, Hestrin S (2001) Electrical synapses between GABA-releasing interneurons. Nat Rev Neurosci 2:425–433

    Article  CAS  PubMed  Google Scholar 

  • Garaschuk O, Linn J, Eilers J, Konnerth A (2000) Large-scale oscillatory calcium waves in the immature cortex. Nat Neurosci 3:452–459

    Article  CAS  PubMed  Google Scholar 

  • Garrett FG, Durham PL (2008) Differential expression of connexins in trigeminal ganglion neurons and satellite glial cells in response to chronic or acute joint inflammation. Neuron Glia Biol 4:295–306

    Article  PubMed Central  PubMed  Google Scholar 

  • Giaume C, Theis M (2010) Pharmacological and genetic approaches to study connexin-mediated channels in glial cells of the central nervous system. Brain Res Rev 63:160–176

    Article  CAS  PubMed  Google Scholar 

  • Guyot LL, Diaz FG, O’Regan MH, McLeod S, Park H, Phillis JW (2001) Real-time measurement of glutamate release from the ischemic penumbra of the rat cerebral cortex using a focal middle cerebral artery occlusion model. Neurosci Lett 299:37–40

    Article  CAS  PubMed  Google Scholar 

  • Hanganu IL, Okabe A, Lessmann V, Luhmann HJ (2009) Cellular mechanisms of subplate-driven and cholinergic input-dependent network activity in the neonatal rat somatosensory cortex. Cereb Cortex 19:89–105

    Article  PubMed  Google Scholar 

  • Hartfield EM, Rinaldi F, Glover CP, Wong LF, Caldwell MA, Uney JB (2011) Connexin 36 expression regulates neuronal differentiation from neural progenitor cells. PLoS One 6:e14746

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hazell AS (2007) Excitotoxic mechanisms in stroke: an update of concepts and treatment strategies. Neurochem Int 50:941–953

    Article  CAS  PubMed  Google Scholar 

  • Hestrin S, Galarreta M (2005) Electrical synapses define networks of neocortical GABAergic neurons. Trends Neurosci 28:304–309

    Article  CAS  PubMed  Google Scholar 

  • Hormuzdi SG, Pais I, LeBeau FE, Towers SK, Rozov A, Buhl EH, Whittington MA, Monyer H (2001) Impaired electrical signaling disrupts gamma frequency oscillations in connexin 36-deficient mice. Neuron 31:487–495

    Article  CAS  PubMed  Google Scholar 

  • Ikonomidou C, Turski L (2002) Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol 1:383–386

    Article  CAS  PubMed  Google Scholar 

  • Johnston MV, Nakajima W, Hagberg H (2002) Mechanisms of hypoxic neurodegeneration in the developing brain. Neuroscientist 8:212–220

    Article  CAS  PubMed  Google Scholar 

  • Kandler K, Katz LC (1998a) Coordination of neuronal activity in developing visual cortex by gap junction-mediated biochemical communication. J Neurosci 18:1419–1427

    CAS  PubMed  Google Scholar 

  • Kandler K, Katz LC (1998b) Relationship between dye coupling and spontaneous activity in developing ferret visual cortex. Dev Neurosci 20:59–64

    Article  CAS  PubMed  Google Scholar 

  • Lee SC, Cruikshank SJ, Connors BW (2010) Electrical and chemical synapses between relay neurons in developing thalamus. J Physiol 588:2403–2415

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lobner D, Choi DW (1994) Dipyridamole increases oxygen-glucose deprivation-induced injury in cortical cell culture. Stroke 25:2085–2089 (discussion 2089–2090)

    Article  CAS  PubMed  Google Scholar 

  • MacVicar BA, Thompson RJ (2010) Non-junction functions of pannexin-1 channels. Trends Neurosci 33:93–102

    Article  CAS  PubMed  Google Scholar 

  • Maher BJ, McGinley MJ, Westbrook GL (2009) Experience-dependent maturation of the glomerular microcircuit. Proc Natl Acad Sci USA 106:16865–16870

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mentis GZ, Diaz E, Moran LB, Navarrete R (2002) Increased incidence of gap junctional coupling between spinal motoneurones following transient blockade of NMDA receptors in neonatal rats. J Physiol 544:757–764

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Morrison B 3rd, Saatman KE, Meaney DF, McIntosh TK (1998) In vitro central nervous system models of mechanically induced trauma: a review. J Neurotrauma 15:911–928

    Article  PubMed  Google Scholar 

  • Nagy JI, Dudek FE, Rash JE (2004) Update on connexins and gap junctions in neurons and glia in the mammalian nervous system. Brain Res Brain Res Rev 47:191–215

    Article  CAS  PubMed  Google Scholar 

  • Nijhawan D, Honarpour N, Wang X (2000) Apoptosis in neural development and disease. Annu Rev Neurosci 23:73–87

    Article  CAS  PubMed  Google Scholar 

  • Oguro K, Jover T, Tanaka H, Lin Y, Kojima T, Oguro N, Grooms SY, Bennett MV, Zukin RS (2001) 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 21:7534–7542

    CAS  PubMed  Google Scholar 

  • Ohsumi A, Nawashiro H, Otani N, Ooigawa H, Toyooka T, Yano A, Nomura N, Shima K (2006) Alteration of gap junction proteins (connexins) following lateral fluid percussion injury in rats. Acta Neurochir Suppl 96:148–150

    Article  CAS  PubMed  Google Scholar 

  • Ozog MA, Siushansian R, Naus CC (2002) Blocked gap junctional coupling increases glutamate-induced neurotoxicity in neuron-astrocyte co-cultures. J Neuropathol Exp Neurol 61:132–141

    CAS  PubMed  Google Scholar 

  • Park W-M, Wang Y, Park S, Denisova JV, Fontes JD, Belousov AB (2011) Interplay of chemical neurotransmitters regulates developmental increase in electrical synapses. J Neurosci 31:5909–5920

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pastor AM, Mentis GZ, De La Cruz RR, Diaz E, Navarrete R (2003) Increased electrotonic coupling in spinal motoneurons after transient botulinum neurotoxin paralysis in the neonatal rat. J Neurophysiol 89:793–805

    Article  PubMed  Google Scholar 

  • Perez Velazquez JL, Valiante TA, Carlen PL (1994) Modulation of gap junctional mechanisms during calcium-free induced field burst activity: a possible role for electrotonic coupling in epileptogenesis. J Neurosci 14:4308–4317

    CAS  PubMed  Google Scholar 

  • Perez Velazquez JL, Frantseva MV, Naus CC (2003) Gap junctions and neuronal injury: protectants or executioners? Neuroscientist 9:5–9

    Article  CAS  PubMed  Google Scholar 

  • Personius KE, Chang Q, Mentis GZ, O’Donovan MJ, Balice-Gordon RJ (2007) Reduced gap junctional coupling leads to uncorrelated motor neuron firing and precocious neuromuscular synapse elimination. Proc Natl Acad Sci USA 104:11808–11813

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rash JE, Kamasawa N, Davidson KG, Yasumura T, Pereda AE, Nagy JI (2012) Connexin composition in apposed gap junction hemiplaques revealed by matched double-replica freeze-fracture replica immunogold labeling. J Membr Biol 245:333–344

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Saez JC, Schalper KA, Retamal MA, Orellana JA, Shoji KF, Bennett MV (2010) Cell membrane permeabilization via connexin hemichannels in living and dying cells. Exp Cell Res 316:2377–2389

    Article  CAS  PubMed  Google Scholar 

  • Saxena S, Caroni P (2011) Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron 71:35–48

    Article  CAS  PubMed  Google Scholar 

  • Sohl G, Maxeiner S, Willecke K (2005) Expression and functions of neuronal gap junctions. Nat Rev Neurosci 6:191–200

    Article  PubMed  Google Scholar 

  • Song J-H, Wang Y, Fontes JD, Belousov AB (2012) Regulation of connexin 36 expression during development. Neurosci Lett 513:17–19

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sosinsky GE, Boassa D, Dermietzel R, Duffy HS, Laird DW, MacVicar B, Naus CC, Penuela S, Scemes E, Spray DC, Thompson RJ, Zhao HB, Dahl G (2011) Pannexin channels are not gap junction hemichannels. Channels 5:193–197

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stein V, Nicoll RA (2003) GABA generates excitement. Neuron 37:375–378

    Article  CAS  PubMed  Google Scholar 

  • Stoffel M, Plesnila N, Eriskat J, Furst M, Baethmann A (2002) Release of excitatory amino acids in the penumbra of a focal cortical necrosis. J Neurotrauma 19:467–477

    Article  PubMed  Google Scholar 

  • Striedinger K, Petrasch-Parwez E, Zoidl G, Napirei M, Meier C, Eysel UT, Dermietzel R (2005) Loss of connexin36 increases retinal cell vulnerability to secondary cell loss. Eur J Neurosci 22:605–616

    Article  PubMed  Google Scholar 

  • Unterberg AW, Stover J, Kress B, Kiening KL (2004) Edema and brain trauma. Neuroscience 129:1021–1029

    Article  CAS  PubMed  Google Scholar 

  • Venance L, Rozov A, Blatow M, Burnashev N, Feldmeyer D, Monyer H (2000) Connexin expression in electrically coupled postnatal rat brain neurons. Proc Natl Acad Sci USA 97:10260–10265

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Y, Denisova JV, Kang KS, Fontes JD, Zhu BT, Belousov AB (2010) Neuronal gap junctions are required for NMDA receptor-mediated excitotoxicity: implications in ischemic stroke. J Neurophysiol 104:3551–3556

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Y, Song J-H, Denisova JV, Park W-M, Fontes JD, Belousov AB (2012) Neuronal gap junction coupling is regulated by glutamate and plays critical role in cell death during neuronal injury. J Neurosci 32:713–725

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wong M, Yamada KA (2001) Developmental characteristics of epileptiform activity in immature rat neocortex: a comparison of four in vitro seizure models. Brain Res Dev Brain Res 128:113–120

    CAS  PubMed  Google Scholar 

  • Yoshioka H, Sugita M, Kinouchi H (2009) Neuroprotective effects of group II metabotropic glutamate receptor agonist DCG-IV on hippocampal neurons in transient forebrain ischemia. Neurosci Lett 461:266–270

    Article  CAS  PubMed  Google Scholar 

  • Yuste R, Nelson DA, Rubin WW, Katz LC (1995) Neuronal domains in developing neocortex: mechanisms of coactivation. Neuron 14:7–17

    Article  CAS  PubMed  Google Scholar 

  • Zhou M, Baudry M (2006) Developmental changes in NMDA neurotoxicity reflect developmental changes in subunit composition of NMDA receptors. J Neurosci 26:2956–2963

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported by NIH (R01 NS064256 and R21 NS076925) and the University of Kansas Medical Center funds to A.B.B.

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  1. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 2146 W. 39th Avenue, M/S 3051, Kansas City, KS, 66160, USA

    Andrei B. Belousov

  2. Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA

    Joseph D. Fontes

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Correspondence to Andrei B. Belousov.

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Belousov, A.B., Fontes, J.D. Neuronal gap junction coupling as the primary determinant of the extent of glutamate-mediated excitotoxicity. J Neural Transm 121, 837–846 (2014). https://doi.org/10.1007/s00702-013-1109-7

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