There are two main modalities of synaptic transmission: chemical and electrical. Although chemical synapses are perceived to be structurally more complex and functionally dynamic than electrical synapses, emerging evidence indicates that electrical synapses might be similarly complex, functionally diverse and highly modifiable.
Far from functioning independently and serving unrelated functions, these two modalities of synaptic transmission closely interact. Rather than conceiving synaptic transmission as either chemical or electrical, this article emphasizes the notion that synaptic transmission is both chemical and electrical, and that interactions between these two forms of interneuronal communication are required for normal brain development and function.
The development of neural circuits in disparate nervous systems (both vertebrate and invertebrate) seems to rely critically on interactions between chemical and electrical synapses, which reciprocally and dynamically regulate the emergence of these two forms of transmission.
During development, interactions between electrical synapses are crucial for the formation of neural circuits; however, such interactions in the adult brain result in dynamic reconfiguration of hardwired networks. The strength of electrical synapses is regulated by neuromodulaters such as dopamine and by glutamatergic synapses in an activity-dependent manner.
Interactions between electrical and chemical synapses are also likely to have important pathological implications. Recapitulation of developmental interactions between chemical and electrical synapses has been observed after brain injury, and dysregulation of electrical synapses by neurotransmitters could contribute to cognitive impairment.
Brain function relies on the ability of neurons to communicate with each other. Interneuronal communication primarily takes place at synapses, where information from one neuron is rapidly conveyed to a second neuron. There are two main modalities of synaptic transmission: chemical and electrical. Far from functioning independently and serving unrelated functions, mounting evidence indicates that these two modalities of synaptic transmission closely interact, both during development and in the adult brain. Rather than conceiving synaptic transmission as either chemical or electrical, this article emphasizes the notion that synaptic transmission is both chemical and electrical, and that interactions between these two forms of interneuronal communication might be required for normal brain development and function.
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Sheng, M., Sabatini, B. L. & Sudhof, T. C. (eds) The Synapse (Cold Spring Harbor Laboratory, 2012).
Bennett, M. V. L. & Zukin, R. S. Electrical coupling and neuronal synchronization in the mammalian brain. Neuron 41, 495–511 (2004).
Zoli, M. et al. The emergence of the volume transmission concept. Brain Res. Brain Res. Rev. 26, 136–147 (1998).
Faber, D. S. & Korn, H. Electrical field effects: their relevance in central neural networks. Physiol. Rev. 69, 821–863 (1989).
Connors, B. W. & Long, M. A. Electrical synapses in the mammalian brain. Annu. Rev. Neurosci. 27, 393–418 (2004).
Galarreta, M. & Hestrin, S. A network of fast-spiking cells in the neocortex connected by electrical synapses. Nature 402, 72–75 (1999).
Gibson, J. R., Beierlein, M. & Connors, B. W. Two networks of electrically coupled inhibitory neurons in neocortex. Nature 402, 75–79 (1999).
Galarreta, M. & Hestrin, S. Electrical synapses between GABA-releasing interneurons. Nature Rev. Neurosci. 2, 425–433 (2001).
Bennett, M. V. Electrical synapses, a personal perspective (or history). Brain Res. Brain Res. Rev. 32, 16–28 (2000).
Bandara, H. M. H. N., Lam, O. L. T., Jin, L. J. & Samaranayake, L. Microbial chemical signaling: a current perspective. Crit. Rev. Microbiol. 38, 217–249 (2012).
Li, Z. & Nair, S. K. Quorum sensing: how bacteria can coordinate activity and synchronize their response to external signals? Protein Sci. 21, 1403–1417 (2012).
Dustin, M. L. Signaling at neuro/immune synapses. J. Clin. Invest. 122, 1149–1155 (2012).
Sterling, P. & Matthews, G. Structure and function of ribbon synapses. Trends Neurosci. 28, 20–29 (2005).
Goodenough, D. A. & Paul, D. L. Gap junctions. Cold Spring Harb. Perspect. Biol. 1, a002576 (2009).
MacVicar, B. A. & Thompson, R. J. Non-junction functions of pannexin-1 channels. Trends Neurosci. 33, 93–102 (2010).
Pereda, A. E. et al. Gap junction-mediated electrical transmission: regulatory mechanisms and plasticity. Biochim. Biophys. Acta 1828, 134–146 (2013).
Shimizu, K. & Stopfer, M. Gap junctions. Curr. Biol. 23, R1026–R1031 (2013).
Söhl, G., Maxeiner, S. & Willecke, K. Expression and functions of neuronal gap junctions. Nature Rev. Neurosci. 6, 191–200 (2005).
Bloomfield, S. A. & Völgyi, B. The diverse functional roles and regulation of neuronal gap junctions in the retina. Nature Rev. Neurosci. 10, 495–506 (2009).
Condorelli, D. F., Belluardo, N., Trovato-Salinaro, A. & Mudò, G. Expression of Cx36 in mammalian neurons. Brain Res. Brain Res. Rev. 32, 72–85 (2000).
Lee, S.-C., Cruikshank, S. J. & Connors, B. W. Electrical and chemical synapses between relay neurons in developing thalamus. J. Physiol. 588, 2403–2415 (2010).
Curti, S., Hoge, G., Nagy, J. I. & Pereda, A. E. Synergy between electrical coupling and membrane properties promotes strong synchronization of neurons of the mesencephalic trigeminal nucleus. J. Neurosci. 32, 4341–4359 (2012).
Phelan, P. Innexins: members of an evolutionarily conserved family of gap-junction proteins. Biochim. Biophys. Acta 1711, 225–245 (2005).
Kandarian, B. et al. The medicinal leech genome encodes 21 innexin genes: different combinations are expressed by identified central neurons. Dev. Genes Evol. 222, 29–44 (2012).
Liu, P. et al. Six innexins contribute to electrical coupling of C. elegans body-wall muscle. PLoS ONE 8, e76877 (2013).
Getting, P. A. Modification of neuron properties by electrotonic synapses. I. Input resistance, time constant, and integration. J. Neurophysiol. 37, 846–857 (1974).
Getting, P. A. & Willows, A. O. Modification of neuron properties by electrotonic synapses. II. Burst formation by electrotonic synapses. J. Neurophysiol. 37, 858–868 (1974).
Galarreta, M. & Hestrin, S. Spike transmission and synchrony detection in networks of GABAergic interneurons. Science 292, 2295–2299 (2001). The authors propose that electrical synapses operate as coincidence detectors in networks of electrically coupled neurons.
Veruki, M. L. & Hartveit, E. All (rod) amacrine cells form a network of electrically coupled interneurons in the mammalian retina. Neuron 33, 935–946 (2002).
DeVries, S. H., Qi, X., Smith, R., Makous, W. & Sterling, P. Electrical coupling between mammalian cones. Curr. Biol. 12, 1900–1907 (2002).
Pereda, A. E., Bell, T. D. & Faber, D. S. Retrograde synaptic communication via gap junctions coupling auditory afferents to the Mauthner cell. J. Neurosci. 15, 5943–5955 (1995).
Curti, S. & Pereda, A. E. Voltage-dependent enhancement of electrical coupling by a subthreshold sodium current. J. Neurosci. 24, 3999–4010 (2004).
Herberholz, J., Antonsen, B. L. & Edwards, D. H. A lateral excitatory network in the escape circuit of crayfish. J. Neurosci. 22, 9078–9085 (2002).
Vervaeke, K., Lorincz, A., Nusser, Z. & Silver, R. A. Gap junctions compensate for sublinear dendritic integration in an inhibitory network. Science 335, 1624–1628 (2012).
Phelan, P. et al. Mutations in shaking-B prevent electrical synapse formation in the Drosophila giant fiber system. J. Neurosci. 16, 1101–1113 (1996).
Edwards, D. H., Heitler, W. J. & Krasne, F. B. Fifty years of a command neuron: the neurobiology of escape behavior in the crayfish. Trends Neurosci. 22, 153–161 (1999).
Faber, D. S. & Pereda, A. E. in Encyclopedia of Fish Physiology: From Genome Environment (ed. Farrell, A.) 73–79 (Elsevier, 2011).
Laird, D. W. Life cycle of connexins in health and disease. Biochem. J. 394, 527–543 (2006).
Laird, D. W. The life cycle of a connexin: gap junction formation, removal, and degradation. J. Bioenerg. Biomembr. 28, 311–318 (1996).
Gumpert, A. M., Varco, J. S., Baker, S. M., Piehl, M. & Falk, M. M. Double-membrane gap junction internalization requires the clathrin-mediated endocytic machinery. FEBS Lett. 582, 2887–2892 (2008).
Piehl, M. et al. Internalization of large double-membrane intercellular vesicles by a clathrin-dependent endocytic process. Mol. Biol. Cell 18, 337–347 (2007).
Lauf, U. et al. Dynamic trafficking and delivery of connexons to the plasma membrane and accretion to gap junctions in living cells. Proc. Natl Acad. Sci. USA 99, 10446–10451 (2002).
Gaietta, G. et al. Multicolor and electron microscopic imaging of connexin trafficking. Science 296, 503–507 (2002).
Flores, C. E. et al. Trafficking of gap junction channels at a vertebrate electrical synapse in vivo. Proc. Natl Acad. Sci. USA 109, E573–E582 (2012). This paper provides the first evidence of the trafficking of gap junction channels in a native electrical synapse.
Pereda, A. E. & Faber, D. S. in Encyclopedia of Fish Physiology: From Genome Environment (ed. Farrell, A.) 66–72 (Elsevier, 2011).
Hervé, J.-C., Derangeon, M., Bahbouhi, B., Mesnil, M. & Sarrouilhe, D. The connexin turnover, an important modulating factor of the level of cell-to-cell junctional communication: comparison with other integral membrane proteins. J. Membr. Biol. 217, 21–33 (2007).
Lüscher, C. et al. Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24, 649–658 (1999). This article provides one of the first descriptions of the existence of trafficking and cycling of receptors at glutamatergic synapses and their potential roles in synaptic plasticity.
Carroll, R. C. & Zukin, R. S. NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity. Trends Neurosci. 25, 571–577 (2002).
Carroll, R. C., Beattie, E. C., von Zastrow, M. & Malenka, R. C. Role of AMPA receptor endocytosis in synaptic plasticity. Nature Rev. Neurosci. 2, 315–324 (2001).
Chen, L. et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000).
Ehlers, M. D. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28, 511–525 (2000).
Pereda, A. E., Rash, J. E., Nagy, J. I. & Bennett, M. V. L. Dynamics of electrical transmission at club endings on the Mauthner cells. Brain Res. Brain Res. Rev. 47, 227–244 (2004).
Dong, H. et al. GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors. Nature 386, 279–284 (1997).
Leonard, A. S., Davare, M. A., Horne, M. C., Garner, C. C. & Hell, J. W. SAP97 is associated with the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit. J. Biol. Chem. 273, 19518–19524 (1998).
Kennedy, M. B. The postsynaptic density at glutamatergic synapses. Trends Neurosci. 20, 264–268 (1997).
Sotelo, C. & Korn, H. Morphological correlates of electrical and other interactions through low-resistance pathways between neurons of the vertebrate central nervous system. Int. Rev. Cytol. 55, 67–107 (1978).
Lynn, B. D., Li, X. & Nagy, J. I. Under construction: building the macromolecular superstructure and signaling components of an electrical synapse. J. Membr. Biol. 245, 303–317 (2012). The authors review the proteins associated with connexin-formed gap junction channels at electrical synapses.
Li, X., Lynn, B. D. & Nagy, J. I. The effector and scaffolding proteins AF6 and MUPP1 interact with connexin36 and localize at gap junctions that form electrical synapses in rodent brain. Eur. J. Neurosci. 35, 166–181 (2012).
Li, X., Lu, S. & Nagy, J. I. Direct association of connexin36 with zonula occludens-2 and zonula occludens-3. Neurochem. Int. 54, 393–402 (2009).
Li, X., Olson, C., Lu, S. & Nagy, J. I. Association of connexin36 with zonula occludens-1 in HeLa cells, βTC-3 cells, pancreas, and adrenal gland. Histochem. Cell Biol. 122, 485–498 (2004).
Li, X. et al. Neuronal connexin36 association with zonula occludens-1 protein (ZO-1) in mouse brain and interaction with the first PDZ domain of ZO-1. Eur. J. Neurosci. 19, 2132–2146 (2004).
Flores, C. E., Li, X., Bennett, M. V. L., Nagy, J. I. & Pereda, A. E. Interaction between connexin35 and zonula occludens-1 and its potential role in the regulation of electrical synapses. Proc. Natl Acad. Sci. USA 105, 12545–12550 (2008).
Alev, C. et al. The neuronal connexin36 interacts with and is phosphorylated by CaMKII in a way similar to CaMKII interaction with glutamate receptors. Proc. Natl Acad. Sci. USA 105, 20964–20969 (2008). The paper provides evidence for the existence of direct protein–protein interactions between gap junction-forming proteins and CaMKII, a regulatory kinase that also regulates chemical synapses.
Flores, C. E. et al. Variability of distribution of Ca2+/calmodulin-dependent kinase II at mixed synapses on the mauthner cell: colocalization and association with connexin 35. J. Neurosci. 30, 9488–9499 (2010).
Hervé, J.-C., Bourmeyster, N. & Sarrouilhe, D. Diversity in protein-protein interactions of connexins: emerging roles. Biochim. Biophys. Acta 1662, 22–41 (2004).
Helbig, I. et al. In vivo evidence for the involvement of the carboxy terminal domain in assembling connexin 36 at the electrical synapse. Mol. Cell. Neurosci. 45, 47–58 (2010).
Rhett, J. M., Jourdan, J. & Gourdie, R. G. Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Mol. Biol. Cell 22, 1516–1528 (2011).
Chen, B., Liu, Q., Ge, Q., Xie, J. & Wang, Z.-W. UNC-1 regulates gap junctions important to locomotion in C. elegans. Curr. Biol. 17, 1334–1339 (2007).
Norman, K. R. & Maricq, A. V. Innexin function: minding the gap junction. Curr. Biol. 17, R812–R814 (2007).
Rash, J. E. et al. Molecular and functional asymmetry at a vertebrate electrical synapse. Neuron 79, 957–969 (2013). The paper provides evidence suggesting that gap junction hemiplaques at electrical synapses might not necessarily be the mirror image of each other.
Phelan, P. et al. Molecular mechanism of rectification at identified electrical synapses in the Drosophila giant fiber system. Curr. Biol. 18, 1955–1960 (2008).
Barrio, L. C. et al. Gap junctions formed by connexins 26 and 32 alone and in combination are differently affected by applied voltage. Proc. Natl Acad. Sci. USA 88, 8410–8414 (1991).
Oh, S., Rubin, J. B., Bennett, M. V., Verselis, V. K. & Bargiello, T. A. Molecular determinants of electrical rectification of single channel conductance in gap junctions formed by connexins 26 and 32. J. Gen. Physiol. 114, 339–364 (1999).
Verselis, V. K., Ginter, C. S. & Bargiello, T. A. Opposite voltage gating polarities of two closely related connexins. Nature 368, 348–351 (1994).
Volff, J.-N. Genome evolution and biodiversity in teleost fish. Heredity (Edinb.) 94, 280–294 (2005).
Kandler, K. & Katz, L. C. Neuronal coupling and uncoupling in the developing nervous system. Curr. Opin. Neurobiol. 5, 98–105 (1995).
Montoro, R. J. & Yuste, R. Gap junctions in developing neocortex: a review. Brain Res. Brain Res. Rev. 47, 216–226 (2004).
Peinado, A., Yuste, R. & Katz, L. C. Extensive dye coupling between rat neocortical neurons during the period of circuit formation. Neuron 10, 103–114 (1993). The paper describes the existence of extensive gap junction coupling and its developmental regulation in the vertebrate brain.
Peinado, A., Yuste, R. & Katz, L. C. Gap junctional communication and the development of local circuits in neocortex. Cereb. Cortex 3, 488–498 (1993).
Penn, A. A., Wong, R. O. & Shatz, C. J. Neuronal coupling in the developing mammalian retina. J. Neurosci. 14, 3805–3815 (1994).
Bittman, K., Owens, D. F., Kriegstein, A. R. & LoTurco, J. J. Cell coupling and uncoupling in the ventricular zone of developing neocortex. J. Neurosci. 17, 7037–7044 (1997).
Yuste, R., Peinado, A. & Katz, L. C. Neuronal domains in developing neocortex. Science 257, 665–669 (1992).
Yuste, R. & Katz, L. C. Control of postsynaptic Ca2+ influx in developing neocortex by excitatory and inhibitory neurotransmitters. Neuron 6, 333–344 (1991).
Marin-Burgin, A., Eisenhart, F. J., Baca, S. M., Kristan, W. B. & French, K. A. Sequential development of electrical and chemical synaptic connections generates a specific behavioral circuit in the leech. J. Neurosci. 25, 2478–2489 (2005).
Marin-Burgin, A., Eisenhart, F. J., Kristan, W. B. & French, K. A. Embryonic electrical connections appear to pre-figure a behavioral circuit in the leech CNS. J. Comp. Physiol. A Neuroethol. Sens. Neural Behav. Physiol. 192, 123–133 (2006).
Wolszon, L. Cell–cell interactions define the innervation patterns of central leech neurons during development. J. Neurobiol. 27, 335–352 (1995).
Chuang, C.-F., Vanhoven, M. K., Fetter, R. D., Verselis, V. K. & Bargmann, C. I. An innexin-dependent cell network establishes left–right neuronal asymmetry in C. elegans. Cell 129, 787–799 (2007).
Baker, M. W., Yazdani, N. & Macagno, E. R. Gap junction-dependent homolog avoidance in the developing CNS. J. Neurosci. 33, 16673–16683 (2013).
Wolszon, L. R., Rehder, V., Kater, S. B. & Macagno, E. R. Calcium wave fronts that cross gap junctions may signal neuronal death during development. J. Neurosci. 14, 3437–3448 (1994).
Wolszon, L. R., Gao, W. Q., Passani, M. B. & Macagno, E. R. Growth cone “collapse” in vivo: are inhibitory interactions mediated by gap junctions? J. Neurosci. 14, 999–1010 (1994).
Wolszon, L. R., Passani, M. B. & Macagno, E. R. Interactions during a critical period inhibit bilateral projections in embryonic neurons. J. Neurosci. 15, 1506–1515 (1995).
Chang, Q., Gonzalez, M., Pinter, M. J. & Balice-Gordon, R. J. Gap junctional coupling and patterns of connexin expression among neonatal at lumbar spinal motor neurons. J. Neurosci. 19, 10813–10828 (1999).
Personius, K., Chang, Q., Bittman, K., Panzer, J. & Balice-Gordon, R. Gap junctional communication among motor and other neurons shapes patterns of neural activity and synaptic connectivity during development. Cell Commun. Adhes. 8, 329–333 (2001).
Walton, K. D. & Navarrete, R. Postnatal changes in motoneurone electrotonic coupling studied in the in vitro rat lumbar spinal cord. J. Physiol. 433, 283–305 (1991).
Colman, H. & Lichtman, J. W. Interactions between nerve and muscle: synapse elimination at the developing neuromuscular junction. Dev. Biol. 156, 1–10 (1993).
Personius, K. E. & Balice-Gordon, R. J. Loss of correlated motor neuron activity during synaptic competition at developing neuromuscular synapses. Neuron 31, 395–408 (2001).
Personius, K. E., Chang, Q., Mentis, G. Z., O'Donovan, M. J. & Balice-Gordon, R. J. Reduced gap junctional coupling leads to uncorrelated motor neuron firing and precocious neuromuscular synapse elimination. Proc. Natl Acad. Sci. USA 104, 11808–11813 (2007).
Szabo, T. M., Faber, D. S. & Zoran, M. J. Transient electrical coupling delays the onset of chemical neurotransmission at developing synapses. J. Neurosci. 24, 112–120 (2004). Using a reduced invertebrate model, the authors unambiguously demonstrate the inter-relationship between the formation of electrical and chemical synapses.
Todd, K. L., Kristan, W. B. Jr & French, K. A. Gap junction expression is required for normal chemical synapse formation. J. Neurosci. 30, 15277–15285 (2010). This study elegantly demonstrates the initial requirement of electrical synapses for the formation of chemical synapses in an in vivo system.
Mentis, G. Z., Díaz, E., Moran, L. B. & Navarrete, R. Increased incidence of gap junctional coupling between spinal motoneurones following transient blockade of NMDA receptors in neonatal rats. J. Physiol. 544, 757–764 (2002). The paper provides evidence for the existence of an inverse relationship between the presence of electrical synapses and chemical synapses in the mammalian brain.
Maher, B. J., McGinley, M. J. & Westbrook, G. L. Experience-dependent maturation of the glomerular microcircuit. Proc. Natl Acad. Sci. USA 106, 16865–16870 (2009). The paper demonstrates the existence of deficits in the formation of circuits formed by chemical synapses in mice lacking the gap junction protein CX36.
Yu, Y.-C. et al. Preferential electrical coupling regulates neocortical lineage-dependent microcircuit assembly. Nature 486, 113–117 (2012).
Curtin, K. D., Zhang, Z. & Wyman, R. J. Gap junction proteins expressed during development are required for adult neural function in the Drosophila optic lamina. J. Neurosci. 22, 7088–7096 (2002).
Wang, Y. & Belousov, A. B. Deletion of neuronal gap junction protein connexin 36 impairs hippocampal LTP. Neurosci. Lett. 502, 30–32 (2011).
Arumugam, H., Liu, X., Colombo, P. J., Corriveau, R. A. & Belousov, A. B. NMDA receptors regulate developmental gap junction uncoupling via CREB signaling. Nature Neurosci. 8, 1720–1726 (2005). The paper describes at the mechanistic level how the emergence of glutamatergic transmission leads to a massive reduction in gap junction coupling in the developing brain.
Park, W.-M. et al. Interplay of chemical neurotransmitters regulates developmental increase in electrical synapses. J. Neurosci. 31, 5909–5920 (2011).
Belousov, A. B. & Fontes, J. D. Neuronal gap junctions: making and breaking connections during development and injury. Trends Neurosci. 36, 227–236 (2013).
Pereda, A., Triller, A., Korn, H. & Faber, D. S. Dopamine enhances both electrotonic coupling and chemical excitatory postsynaptic potentials at mixed synapses. Proc. Natl Acad. Sci. USA 89, 12088–12092 (1992).
Pereda, A. E., Nairn, A. C., Wolszon, L. R. & Faber, D. S. Postsynaptic modulation of synaptic efficacy at mixed synapses on the Mauthner cell. J. Neurosci. 14, 3704–3712 (1994).
Piccolino, M., Neyton, J. & Gerschenfeld, H. M. Decrease of gap junction permeability induced by dopamine and cyclic adenosine 3′:5′-monophosphate in horizontal cells of turtle retina. J. Neurosci. 4, 2477–2488 (1984).
Lasater, E. M. & Dowling, J. E. Dopamine decreases conductance of the electrical junctions between cultured retinal horizontal cells. Proc. Natl Acad. Sci. USA 82, 3025–3029 (1985).
Urschel, S. et al. Protein kinase A-mediated phosphorylation of connexin36 in mouse retina results in decreased gap junctional communication between AII amacrine cells. J. Biol. Chem. 281, 33163–33171 (2006).
Kothmann, W. W., Li, X., Burr, G. S. & O'Brien, J. Connexin 35/36 is phosphorylated at regulatory sites in the retina. Vis. Neurosci. 24, 363–375 (2007).
Kothmann, W. W., Massey, S. C. & O'Brien, J. Dopamine-stimulated dephosphorylation of connexin 36 mediates AII amacrine cell uncoupling. J. Neurosci. 29, 14903–14911 (2009).
Ribelayga, C., Cao, Y. & Mangel, S. C. The circadian clock in the retina controls rod-cone coupling. Neuron 59, 790–801 (2008).
Zsiros, V. & Maccaferri, G. Noradrenergic modulation of electrical coupling in GABAergic networks of the hippocampus. J. Neurosci. 28, 1804–1815 (2008).
Rörig, B. & Sutor, B. Serotonin regulates gap junction coupling in the developing rat somatosensory cortex. Eur. J. Neurosci. 8, 1685–1695 (1996).
Johnson, B. R., Peck, J. H. & Harris-Warrick, R. M. Amine modulation of electrical coupling in the pyloric network of the lobster stomatogastric ganglion. J. Comp. Physiol. A 172, 715–732 (1993).
Hatton, G. I. & Yang, Q. Z. Synaptically released histamine increases dye coupling among vasopressinergic neurons of the supraoptic nucleus: mediation by H1 receptors and cyclic nucleotides. J. Neurosci. 16, 123–129 (1996).
O'Donnell, P. & Grace, A. A. Cortical afferents modulate striatal gap junction permeability via nitric oxide. Neuroscience 76, 1–5 (1997).
Rörig, B. & Sutor, B. Nitric oxide-stimulated increase in intracellular cGMP modulates gap junction coupling in rat neocortex. Neuroreport 7, 569–572 (1996).
Bargmann, C. I. Beyond the connectome: how neuromodulators shape neural circuits. Bioessays 34, 458–465 (2012).
Xia, X.-B. & Mills, S. L. Gap junctional regulatory mechanisms in the AII amacrine cell of the rabbit retina. Vis. Neurosci. 21, 791–805 (2004).
Mills, S. L. & Massey, S. C. Differential properties of two gap junctional pathways made by AII amacrine cells. Nature 377, 734–737 (1995).
Pereda, A. et al. Connexin35 mediates electrical transmission at mixed synapses on Mauthner cells. J. Neurosci. 23, 7489–7503 (2003).
Yang, X. D., Korn, H. & Faber, D. S. Long-term potentiation of electrotonic coupling at mixed synapses. Nature 348, 542–545 (1990). This study provides the first evidence for the existence of activity-dependent potentiation in electrical synapses.
Pereda, A. E. & Faber, D. S. Activity-dependent short-term enhancement of intercellular coupling. J. Neurosci. 16, 983–992 (1996).
Pereda, A. E. et al. Ca2+/calmodulin-dependent kinase II mediates simultaneous enhancement of gap-junctional conductance and glutamatergic transmission. Proc. Natl Acad. Sci. USA 95, 13272–13277 (1998). The paper provides the first evidence for the role of CaMKII in regulating electrical transmission.
Del Corsso, C., Iglesias, R., Zoidl, G., Dermietzel, R. & Spray, D. C. Calmodulin dependent protein kinase increases conductance at gap junctions formed by the neuronal gap junction protein connexin36. Brain Res. 1487, 69–77 (2012).
Kothmann, W. W. et al. Nonsynaptic NMDA receptors mediate activity-dependent plasticity of gap junctional coupling in the AII amacrine cell network. J. Neurosci. 32, 6747–6759 (2012).
Lisman, J., Yasuda, R. & Raghavachari, S. Mechanisms of CaMKII action in long-term potentiation. Nature Rev. Neurosci. 13, 169–182 (2012).
Hoge, G. J. et al. The extent and strength of electrical coupling between inferior olivary neurons is heterogeneous. J. Neurophysiol. 105, 1089–1101 (2011).
Rash, J. E. et al. High-resolution proteomic mapping in the vertebrate central nervous system: close proximity of connexin35 to NMDA glutamate receptor clusters and co-localization of connexin36 with immunoreactivity for zonula occludens protein-1 (ZO-1). J. Neurocytol. 33, 131–151 (2004).
Urbano, F. J., Leznik, E. & Llinás, R. R. Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling. Proc. Natl Acad. Sci. USA 104, 12554–12559 (2007).
Hatton, G. I. & Yang, Q. Z. Activation of excitatory amino acid inputs to supraoptic neurons. I. Induced increases in dye-coupling in lactating, but not virgin or male rats. Brain Res. 513, 264–269 (1990).
Landisman, C. E. & Connors, B. W. Long-term modulation of electrical synapses in the mammalian thalamus. Science 310, 1809–1813 (2005).
Smith, M. & Pereda, A. E. Chemical synaptic activity modulates nearby electrical synapses. Proc. Natl Acad. Sci. USA 100, 4849–4854 (2003).
Vervaeke, K. et al. Rapid desynchronization of an electrically coupled interneuron network with sparse excitatory synaptic input. Neuron 67, 435–451 (2010).
Cachope, R., Mackie, K., Triller, A., O'Brien, J. & Pereda, A. E. Potentiation of electrical and chemical synaptic transmission mediated by endocannabinoids. Neuron 56, 1034–1047 (2007). The article describes interactions between glutamatergic, dopaminergic and electrical synapses, demonstrating a complex functional inter-relationship between chemical and electrical transmission.
Llinas, R., Baker, R. & Sotelo, C. Electrotonic coupling between neurons in cat inferior olive. J. Neurophysiol. 37, 560–571 (1974).
Best, A. R. & Regehr, W. G. Inhibitory regulation of electrically coupled neurons in the inferior olive is mediated by asynchronous release of GABA. Neuron 62, 555–565 (2009).
Spira, M. E., Spray, D. C. & Bennett, M. V. Electrotonic coupling: effective sign reversal by inhibitory neurons. Science 194, 1065–1067 (1976).
Bartos, M. et al. Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks. Proc. Natl Acad. Sci. USA 99, 13222–13227 (2002).
Buzsáki, G. & Wang, X.-J. Mechanisms of gamma oscillations. Annu. Rev. Neurosci. 35, 203–225 (2012).
Mas, C. et al. Association of the connexin36 gene with juvenile myoclonic epilepsy. J. Med. Genet. 41, e93 (2004). This study provides the first evidence of the relationship between CX36 and juvenile myoclonic epilepsy.
Hempelmann, A., Heils, A. & Sander, T. Confirmatory evidence for an association of the connexin-36 gene with juvenile myoclonic epilepsy. Epilepsy Res. 71, 223–228 (2006).
Dudek, F. E., Snow, R. W. & Taylor, C. P. Role of electrical interactions in synchronization of epileptiform bursts. Adv. Neurol. 44, 593–617 (1986).
Nakazawa, K. et al. GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology 62, 1574–1583 (2012).
Steriade, M. Synchronized activities of coupled oscillators in the cerebral cortex and thalamus at different levels of vigilance. Cereb. Cortex 7, 583–604 (1997).
Hormuzdi, S. G. et al. Impaired electrical signaling disrupts gamma frequency oscillations in connexin 36-deficient mice. Neuron 31, 487–495 (2001). The study provides evidence for the contribution of electrical coupling between cortical inhibitory interneurons in the generation of gamma oscillations, which are associated with cognitive phenomena.
Gonzalez-Burgos, G., Hashimoto, T. & Lewis, D. A. Alterations of cortical GABA neurons and network oscillations in schizophrenia. Curr. Psychiatry Rep. 12, 335–344 (2010).
Hammond, C., Bergman, H. & Brown, P. Pathological synchronization in Parkinson's disease: networks, models and treatments. Trends Neurosci. 30, 357–364 (2007).
Welsh, J. P., Ahn, E. S. & Placantonakis, D. G. Is autism due to brain desynchronization? Int. J. Dev. Neurosci. 23, 253–263 (2005).
Moghaddam, B. Bringing order to the glutamate chaos in schizophrenia. Neuron 40, 881–884 (2003).
Javitt, D. C. et al. Translating glutamate: from pathophysiology to treatment. Sci. Transl. Med. 3, 102mr2 (2011).
Moghaddam, B. & Javitt, D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37, 4–15 (2012).
Nieoullon, A. Dopamine and the regulation of cognition and attention. Prog. Neurobiol. 67, 53–83 (2002).
Penzes, P., Buonanno, A., Passafaro, M., Sala, C. & Sweet, R. A. Developmental vulnerability of synapses and circuits associated with neuropsychiatric disorders. J. Neurochem. 126, 165–182 (2013).
Chang, Q., Pereda, A., Pinter, M. J. & Balice-Gordon, R. J. Nerve injury induces gap junctional coupling among axotomized adult motor neurons. J. Neurosci. 20, 674–684 (2000).
Wang, Y. et al. Neuronal gap junction coupling is regulated by glutamate and plays critical role in cell death during neuronal injury. J. Neurosci. 32, 713–725 (2012). The authors describe the relationship between glutamate and increased gap junctional coupling observed after neuronal injury and its underlying mechanisms.
Hazell, A. S. Excitotoxic mechanisms in stroke: an update of concepts and treatment strategies. Neurochem. Int. 50, 941–953 (2007).
Belousov, A. B. et al. Neuronal gap junctions play a role in the secondary neuronal death following controlled cortical impact. Neurosci. Lett. 524, 16–19 (2012).
Wang, Y. et al. Neuronal gap junctions are required for NMDA receptor-mediated excitotoxicity: implications in ischemic stroke. J. Neurophysiol. 104, 3551–3556 (2010).
Belousov, A. B. Novel model for the mechanisms of glutamate-dependent excitotoxicity: role of neuronal gap junctions. Brain Res. 1487, 123–130 (2012).
Sabatini, B. L. & Regehr, W. G. Timing of neurotransmission at fast synapses in the mammalian brain. Nature 384, 170–172 (1996).
Rash, J. E. et al. Mixed synapses discovered and mapped throughout mammalian spinal cord. Proc. Natl Acad. Sci. USA 93, 4235–4239 (1996).
Hamzei-Sichani, F. et al. Mixed electrical–chemical synapses in adult rat hippocampus are primarily glutamatergic and coupled by connexin-36. Front. Neuroanat. 6, 13 (2012).
Vivar, C., Traub, R. D. & Gutiérrez, R. Mixed electrical–chemical transmission between hippocampal mossy fibers and pyramidal cells. Eur. J. Neurosci. 35, 76–82 (2012).
Fukuda, T. & Kosaka, T. Gap junctions linking the dendritic network of GABAergic interneurons in the hippocampus. J. Neurosci. 20, 1519–1528 (2000).
Valenstein, E. S. The War of the Soups and the Sparks: The Discovery of Neurotransmitters and the Dispute Over How Nerves Communicate (Columbia Univ. Press, 2006).
Elliott, T. R. The action of adrenalin. J. Physiol. 32, 401–467 (1905).
Loewi, O. Über humorale Übertragbarkeit der Herznervenwirkung. Pflugers Arch. Gesamte Physiol. Menschen Tiere 204, 629–640 (in German) (1924).
Sherrington, C. S. The Integrative Action of the Nervous System — Primary Source Edition (Nabu, 2013).
Katz, B. The Release of Neural Transmitter Substances (Sherrington Lecture) (Liverpool Univ. Press, 1969).
Furshpan, E. J. & Potter, D. D. Transmission at the giant motor synapses of the crayfish. J. Physiol. 145, 289–325 (1959).
Bennett, M. V., Aljure, E., Nakajima, Y. & Pappas, G. D. Electrotonic junctions between teleost spinal neurons: electrophysiology and ultrastructure. Science 141, 262–264 (1963).
Robertson, J. D., Bodenheimer, T. S. & Stage, D. E. The ultrastructure of Mauthner cell synapses and nodes in goldfish brains. J. Cell Biol. 19, 159–199 (1963).
Furshpan, E. J. “Electrical transmission” at an excitatory synapse in a vertebrate brain. Science 144, 878–880 (1964).
This research was supported by US National Institutes of Health grants DC03186, DC011099, NS055726, NS085772 and NS0552827 to A.E.P.
The author declares no competing financial interests.
- Lateral excitation
The ability of an excited neuron (or sensory afferent) to excite its neighbours. Although it reduces discrimination, lateral excitation greatly enhances input sensitivity. It is a less-appreciated property of sensory and cortical networks.
- Escape networks
Neural networks found in invertebrate and vertebrate nervous systems (usually containing a small number of cells that include sensory and motor neurons) that seem optimized to mediate fast escape behaviours.
- Mauthner cell
A large reticulospinal neuron found in teleost fish that mediates (among other functions) tail-flip sensory-evoked escape responses.
- Postsynaptic density
(PSD). Originally named after its identification by electron microscopy, the term refers to a macromolecular complex that supports postsynaptic function at chemical synapses and includes neurotransmitters receptors, scaffolding proteins and regulatory signalling molecules.
(Postsynaptic density protein 95). A protein that contains multiple domains that mediate its association with receptors, cell-adhesion molecules and cytoplasmic signalling molecules. By virtue of these interactions, it influences the surface delivery, stability and subcellular location of postsynaptic receptors, and facilitates their functional coupling to downstream signalling pathways.
An extracellularly recorded electrical response that reflects the activation of various cells in the retina (including photoreceptors, inner retinal cells and the output ganglion cells) in response to visual stimulation.
- ON bipolar cells
Retinal cells that functionally link photoreceptors (cones and rods) to ganglion cells. ON bipolar cells are excited by the release of glutamate from photoreceptors, whereas OFF bipolar cells are instead inhibited.
- All type amacrine cells
The AII is a type of amacrine cell (a class of retinal interneuron) that relays rod-driven information through the ON-centre cone bipolar axons to ON-centre ganglion cells (output neurons of the retina) via electrical synapses.
- Associative binding
The term refers to tasks of episodic memory that require the associative combining of distinct components into a compound episode.
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Pereda, A. Electrical synapses and their functional interactions with chemical synapses. Nat Rev Neurosci 15, 250–263 (2014). https://doi.org/10.1038/nrn3708
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