Difference between revisions of "Draft:Two Forms of Electrical Transmission Between Neurons"

Seminal experiments in fish (Robertson et al., 1963<ref>Robertson, J. D., Bodenheimer, T. S., and Stage, D. E. (1963). The ultrastructure of mauthner cell synapses and nodes in goldfish brains. ''J. Cell Biol.'' 19, 159–199. doi: 10.1083/jcb.19.1.159</ref>; Robertson, 1963<ref>Robertson, J. D. (1963). The occurrence of a subunit pattern in the unit membranes of club endings in mauthner cell synapses in goldfish brains. ''J. Cell Biol.'' 19, 201–221. doi: 10.1083/jcb.19.1.201</ref>; Furshpan, 1964<ref name=":5" />; Pappas and Bennett, 1966<ref name=":7">Pappas, G. D., and Bennett, M. V. (1966). Specialized junctions involved in electrical transmission between neurons. ''Ann. N Y Acad. Sci.'' 137, 495–508. doi: 10.1111/j.1749-6632.1966.tb50177.x</ref>; reviewed in Pereda and Bennett, 2017<ref>Pereda, A. E., and Bennett, M. V. L. (2017). “Electrical synapses in fish: relevance to synaptic transmission,” in ''Electrical Coupling and Microcircuits: Network Functions and Plasticity'', ed. J. Jing (London, UK: Academic Press), 1–18.</ref>) led to the identification of the intercellular structure that serves as a pathway of low resistance for the spread of currents between neurons: the “gap junction.” Convergent evidence for the role of these structures in mediating electrical coupling was obtained in the heart (reviewed in Delmar et al., 2004<ref>Delmar, M., Duffy, H. S., Sorgen, P. L., Taffet, S. M., and Spray, D. C. (2004). “Molecular organization and regulation of the cardiac gap junction channel connexin43,” in ''Cardiac Electrophysiol'', eds D. P. Zipes and J. Jalife (Philadelphia: W.B. Saunders), 66–76.</ref>). Gap junctions are groupings of tightly clustered intercellular channels ​(Figure3A) that allow diffusion of intracellular ions carrying electrical currents (Goodenough and Paul, 2009<ref name=":6">Goodenough, D. A., and Paul, D. L. (2009). Gap junctions. ''Cold Spring Harb. Perspect. Biol.'' 1:a002576. doi: 10.1101/cshperspect.a002576</ref>). The intercellular channel is formed by the docking of two apposed individual channels, named “hemichannels” or “connexons,” one contributed by each of the coupled cells (Figure3A). Hemichannels are hexamers made of connexins, a family of 21 genes in humans. Gap junctions are not exclusive to neurons, and they are present in virtually every tissue of an organism, acting as aqueous pores for metabolic support and chemical signaling (Goodenough and Paul, 2009<ref name=":6" />). Only a minority of the connexins (Cxs) are expressed in neurons: Cx36, Cx45, Cx57, Cx30.2 and Cx50 (Söhl et al., 2005<ref>Söhl, G., Maxeiner, S., and Willecke, K. (2005). Expression and functions of neuronal gap junctions. ''Nat. Rev. Neurosci.'' 6, 191–200. doi: 10.1038/nrn1627</ref>; O’Brien, 2014<ref>O’Brien, J. (2014). The ever-changing electrical synapse. ''Curr. Opin. Neurobiol.'' 29, 64–72. doi: 10.1016/j.conb.2014.05.011</ref>; Miller and Pereda, 2017<ref>Miller, A. C., and Pereda, A. E. (2017). The electrical synapse: molecular complexities at the gap and beyond. ''Dev. Neurobiol.'' 77, 562–574. doi: 10.1002/dneu.22484</ref>; Nagy et al., 2018<ref>Nagy, J. I., Pereda, A. E., and Rash, J. E. (2018). Electrical synapses in mammalian CNS: past eras, present focus and future directions. ''Biochim. Biophys. Acta Biomembr.''1860, 102–123. doi: 10.1016/j.bbamem.2017.05.019</ref>). Amongst them, Cx36 (Condorelli et al., 1998<ref>Condorelli, D. F., Parenti, R., Spinella, F., Trovato Salinaro, A., Belluardo, N., Cardile, V., et al. (1998). Cloning of a new gap junction gene (Cx36) highly expressed in mammalian brain neurons. ''Eur. J. Neurosci.'' 10, 1202–1208. doi: 10.1046/j.1460-9568.1998.00163.x</ref>) is considered the main gap junction protein supporting electrical transmission in vertebrates. Except for microglia (Dobrenis et al., 2005<ref>Dobrenis, K., Chang, H.-Y., Pina-Benabou, M. H., Woodroffe, A., Lee, S. C., Rozental, R., et al. (2005). Human and mouse microglia express connexin36 and functional gap junctions are formed between rodent microglia and neurons. ''J. Neurosci. Res.'' 82, 306–315. doi: 10.1002/jnr.20650</ref>) and other cells of ectodermic origin such as pancreatic beta cells (Moreno et al., 2005<ref>Moreno, A. P., Berthoud, V. M., Pérez-Palacios, G., and Pérez-Armendariz, E. M. (2005). Biophysical evidence that connexin-36 forms functional gap junction channels between pancreatic mouse β-cells. ''Am. J. Physiol. Endocrinol. Metab.'' 288, E948–E956. doi: 10.1152/ajpendo.00216.2004</ref>) and chromaffin cells (Martin et al., 2001<ref>Martin, A. O., Mathieu, M. N., Chevillard, C., and Guérineau, N. C. (2001). Gap junctions mediate electrical signaling and ensuing cytosolic Ca2+ increases between chromaffin cells in adrenal slices: a role in catecholamine release. ''J. Neurosci.'' 21, 5397–5405. doi: 10.1523/jneurosci.21-15-05397.2001</ref>), its expression is restricted to neurons (Rash et al., 2000<ref>Rash, J. E., Staines, W. A., Yasumura, T., Patel, D., Furman, C. S., Stelmack, G. L., et al. (2000). Immunogold evidence that neuronal gap junctions in adult rat brain and spinal cord contain connexin-36 but not connexin-32 or connexin-43. ''Proc. Natl. Acad. Sci. U S A'' 97, 7573–7578. doi: 10.1073/pnas.97.13.7573</ref>). Combined, its widespread distribution and neuronal preference make Cx36 and its vertebrate orthologs the main channel-forming protein of neuronal gap junctions. Interestingly, a similar clustered organization of intercellular channels was found at invertebrate gap junctions, where the channels are formed by a different protein named “innexin,” a family of about 20 genes in ''C. elegans'' and 8 genes in the fly (Phelan et al., 1998<ref>Phelan, P., Stebbings, L. A., Baines, R. A., Bacon, J. P., Davies, J. A., and Ford, C. (1998). ''Drosophila'' shaking-B protein forms gap junctions in paired xenopus oocytes. ''Nature''391, 181–184. doi: 10.1038/34426</ref>; Phelan, 2005<ref>Phelan, P. (2005). Innexins: members of an evolutionarily conserved family of gap-junction proteins. ''Biochim. Biophys. Acta'' 1711, 225–245. doi: 10.1016/j.bbamem.2004.10.004</ref>). Innexins form either hexameric or octameric hemichannels (Oshima et al., 2016<ref>Oshima, A., Tani, K., and Fujiyoshi, Y. (2016). Atomic structure of the innexin-6 gap junction channel determined by cryo-EM. ''Nat. Commun.'' 7:13681. doi: 10.1038/ncomms13681</ref>; Skerrett and Williams, 2017<ref name=":8">Skerrett, I. M., and Williams, J. B. (2017). A structural and functional comparison of gap junction channels composed of connexins and innexins. ''Dev. Neurobiol.'' 77, 522–547. doi: 10.1002/dneu.22447</ref>). Remarkably, despite their unrelated sequences, connexins and innexins share a similar membrane topology and converge into similar structures with largely overlapping functions (Pereda and Macagno, 2017<ref>Pereda, A. E., and Macagno, E. (2017). Electrical transmission: two structures, same functions? ''Dev. Neurobiol.'' 77, 517–521. doi: 10.1002/dneu.22488</ref>; Skerrett and Williams, 2017<ref name=":8" />). There is a family of three genes found in vertebrates that share sequence similarities with innexins, the so-called “pannexins” (Panchin et al., 2000<ref>Panchin, Y., Kelmanson, I., Matz, M., Lukyanov, K., Usman, N., and Lukyanov, S. (2000). A ubiquitous family of putative gap junction molecules. ''Curr. Biol.'' 10, R473–R474. doi: 10.1016/s0960-9822(00)00576-5</ref>). Pannexins were found to be expressed in neurons (Bruzzone et al., 2003<ref>Bruzzone, R., Hormuzdi, S. G., Barbe, M. T., Herb, A., and Monyer, H. (2003). Pannexins, a family of gap junction proteins expressed in brain. ''Proc. Natl. Acad. Sci. U S A'' 100, 13644–13649. doi: 10.1073/pnas.2233464100</ref>; Thompson et al., 2008<ref>Thompson, R. J., Jackson, M. F., Olah, M. E., Rungta, R. L., Hines, D. J., Beazely, M. A., et al. (2008). Activation of Pannexin-1 hemichannels augments aberrant bursting in the hippocampus. ''Science'' 322, 1555–1559. doi: 10.1126/science.1165209</ref>), although there is no evidence so far indicating they form gap junctions ''in vivo'' and are capable of supporting electrical communication between neurons. Rather, they are thought to contribute functionally, operating as hemichannels (Dahl and Locovei, 2006<ref>Dahl, G., and Locovei, S. (2006). Pannexin: to gap or not to gap, is that a question? ''IUBMB Life'' 58, 409–419. doi: 10.1080/15216540600794526</ref>; MacVicar and Thompson, 2010<ref>MacVicar, B. A., and Thompson, R. J. (2010). Non-junction functions of pannexin-1 channels. ''Trends Neurosci.'' 33, 93–102. doi: 10.1016/j.tins.2009.11.007</ref>).

From the functional point of view, gap junction channels most commonly operate electrically as ohmic resistors, providing bidirectional communication for electrical signals between two or more cells ​(Figure3B). Currents underlying action potentials in a presynaptic cell can directly flow via the gap junction to the postsynaptic cell, generating “electrical synaptic potentials” or “coupling potentials,” which also are known as “spikelets” ​(Figure1B, middle). Not only currents underlying action potentials but also those responsible for subthreshold signals such as synaptic potentials of either depolarizing or hyperpolarizing nature can spread to the postsynaptic cell to generate a coupling potential ​(Figure3B). The strength or weight of the postsynaptic cell’s response and the passive properties of the coupled cells are largely interdependent (Bennett, 1966<ref>Bennett, M. V. (1966). Physiology of electrotonic junctions. ''Ann. N Y Acad. Sci.'' 137, 509–539. doi: 10.1111/j.1749-6632.1966.tb50178.x</ref>; Getting, 1974<ref>Getting, P. A. (1974). Modification of neuron properties by electrotonic synapses. I. input resistance, time constant and integration. ''J. Neurophysiol.'' 37, 846–857. doi: 10.1152/jn.1974.37.5.846</ref>). Accordingly, the amplitude of the coupling potential is determined not only by the conductance of the gap junction channels but also by the input resistance of the postsynaptic cell (see Bennett, 1966<ref name=":7" />). In addition, the passive properties of the postsynaptic cell impose limitations to the transmission of presynaptic signals, depending on their duration. Short lasting signals such as action potentials are more attenuated than longer lasting signals such as synaptic potentials or afterhyperpolarizations due to the filtering properties of the postsynaptic membrane which are reflected by the membrane “time constant” of the cell (a parameter determined by the product of the cell’s resistance and capacitance that expresses how rapidly the resting membrane potential of the cell can be modified by a given current). As a result, the “coupling coefficient,” a measure of the synaptic strength, defined as the ratio between the amplitude of the postsynaptic coupling potential and that of the presynaptic signal, can be dramatically different for signals with different time courses.