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Difference between revisions of "Draft:Two Forms of Electrical Transmission Between Neurons"
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| width="99%" | <div style="border-radius: 8px; border: 1px solid #73AD21; padding: 8px; background-color: #ECFCEC; font-size: 86%; font-weight:200;">Free resource by '''Donald S. Faber · Alberto E. Pereda '''</div> | | width="99%" | <div style="border-radius: 8px; border: 1px solid #73AD21; padding: 8px; background-color: #ECFCEC; font-size: 86%; font-weight:200;">Free resource by '''Donald S. Faber · Alberto E. Pereda '''</div> | ||
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<br>Donald S. Faber<sup>1,2</sup> and Alberto E. Pereda<sup>1,2*</sup> | <br>Donald S. Faber<sup>1,2</sup> and Alberto E. Pereda<sup>1,2*</sup> | ||
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Finally a set of elegant experiments by Katz, Fatt, Miledi and colleagues showed that chemical transmission is mediated by a Ca++-dependent electrically regulated form of release of neurotransmitter packets (Katz, 1969<ref>Katz, B. (1969). “The release of neural transmitter substances,” in ''Sherrington Lecture'', (Liverpool: Liverpool University Press).</ref>), which in turn are capable of generating an electrical signal in the postsynaptic cell by acting specifically on ligand-gated ion channels known as “receptors” (Figure1B, left). It is now recognized that both modes of communication, electrical and chemical, are operative (Figure 1B). | Finally a set of elegant experiments by Katz, Fatt, Miledi and colleagues showed that chemical transmission is mediated by a Ca++-dependent electrically regulated form of release of neurotransmitter packets (Katz, 1969<ref>Katz, B. (1969). “The release of neural transmitter substances,” in ''Sherrington Lecture'', (Liverpool: Liverpool University Press).</ref>), which in turn are capable of generating an electrical signal in the postsynaptic cell by acting specifically on ligand-gated ion channels known as “receptors” (Figure1B, left). It is now recognized that both modes of communication, electrical and chemical, are operative (Figure 1B). | ||
=== Synaptic Transmission Mediated by Pathways of Low Resistance: Gap Junctions === | === Synaptic Transmission Mediated by Pathways of Low Resistance: Gap Junctions === | ||
As discussed above, Paul Fatt suggested that electrical currents generated in one neuron could directly spread to an adjacent postsynaptic cell via a pathway of low resistance. This idea led to the demonstration that, as postulated, presynaptic electrical currents can at some contacts propagate to the postsynaptic cell “electrotonically.” Moreover, not only action potentials (as are most often required for chemical transmission) but also subthreshold signals were conducted to the postsynaptic cell. In other words, changes in the membrane potential in one cell were capable of spreading to a second cell, generating potentials of similar time course but smaller amplitude, as if the two cells were “electrically coupled.” Electrotonic transmission was observed in both invertebrate (Watanabe, 1958; Furshpan and Potter, 1959) and vertebrate (Bennett et al., 1959; Furshpan, 1964) nervous systems. | As discussed above, Paul Fatt suggested that electrical currents generated in one neuron could directly spread to an adjacent postsynaptic cell via a pathway of low resistance. This idea led to the demonstration that, as postulated, presynaptic electrical currents can at some contacts propagate to the postsynaptic cell “electrotonically.” Moreover, not only action potentials (as are most often required for chemical transmission) but also subthreshold signals were conducted to the postsynaptic cell. In other words, changes in the membrane potential in one cell were capable of spreading to a second cell, generating potentials of similar time course but smaller amplitude, as if the two cells were “electrically coupled.” Electrotonic transmission was observed in both invertebrate (Watanabe, 1958<ref>Watanabe, A. (1958). The interaction of electrical activity among neurons of lobster cardiac ganglion. ''Jpn. J. Physiol.'' 8, 305–318. doi: 10.2170/jjphysiol.8.305</ref>; Furshpan and Potter, 1959<ref>Furshpan, E. J., and Potter, D. D. (1959). Transmission at the giant motor synapses of the crayfish. ''J. Physiol.'' 145, 289–325. doi: 10.1113/jphysiol.1959.sp006143</ref>) and vertebrate (Bennett et al., 1959<ref>Bennett, M. V., Crain, S. M., and Grundfest, H. (1959). Electrophysiology of supramedullary neurons in spheroides maculatus. III. organization of the supramedullary neurons. ''J. Gen. Physiol.'' 43, 221–250. doi: 10.1085/jgp.43.1.221</ref>; Furshpan, 1964<ref name=":5">Furshpan, E. J. (1964). “Electrical transmission” at an excitatory synapse in a vertebrate brain. ''Science''144, 878–880. doi: 10.1126/science.144.3620.878</ref>) nervous systems. | ||
Seminal experiments in fish (Robertson et al., 1963; Robertson, 1963; Furshpan, 1964; Pappas and Bennett, 1966; reviewed in Pereda and Bennett, 2017) 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). Gap junctions are groupings of tightly clustered intercellular channels (Figure3A) that allow diffusion of intracellular ions carrying electrical currents (Goodenough and Paul, 2009). 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). Only a minority of the connexins (Cxs) are expressed in neurons: Cx36, Cx45, Cx57, Cx30.2 and Cx50 (Söhl et al., 2005; O’Brien, 2014; Miller and Pereda, 2017; Nagy et al., 2018). Amongst them, Cx36 (Condorelli et al., 1998) is considered the main gap junction protein supporting electrical transmission in vertebrates. Except for microglia (Dobrenis et al., 2005) and other cells of ectodermic origin such as pancreatic beta cells (Moreno et al., 2005) and chromaffin cells (Martin et al., 2001), its expression is restricted to neurons (Rash et al., 2000). 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; Phelan, 2005). Innexins form either hexameric or octameric hemichannels (Oshima et al., 2016; Skerrett and Williams, 2017). 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; Skerrett and Williams, 2017). There is a family of three genes found in vertebrates that share sequence similarities with innexins, the so-called “pannexins” (Panchin et al., 2000). Pannexins were found to be expressed in neurons (Bruzzone et al., 2003; Thompson et al., 2008), 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; MacVicar and Thompson, 2010). | 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>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; Miller and Pereda, 2017; Nagy et al., 2018). Amongst them, Cx36 (Condorelli et al., 1998) is considered the main gap junction protein supporting electrical transmission in vertebrates. Except for microglia (Dobrenis et al., 2005) and other cells of ectodermic origin such as pancreatic beta cells (Moreno et al., 2005) and chromaffin cells (Martin et al., 2001), its expression is restricted to neurons (Rash et al., 2000). 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; Phelan, 2005). Innexins form either hexameric or octameric hemichannels (Oshima et al., 2016; Skerrett and Williams, 2017). 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; Skerrett and Williams, 2017). There is a family of three genes found in vertebrates that share sequence similarities with innexins, the so-called “pannexins” (Panchin et al., 2000). Pannexins were found to be expressed in neurons (Bruzzone et al., 2003; Thompson et al., 2008), 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; MacVicar and Thompson, 2010). | ||
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; Getting, 1974). 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). 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. | 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; Getting, 1974). 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). 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. | ||