- Email: [email protected]
Electrical Synapses: Rectification Demystified
Current Biology Vol 19 No 1 R34
the food being withdrawn, confirmed these findings and again revealed that the feeding choices of females were conditional upon whether they were feeding alone or in a pair. Why are females conditionally cooperative whereas males are not so inclined? Interestingly the males were observed to behave aggressively towards the females quite often after removal of the food or when the client left. This aggressive behaviour could be an evolved mechanism of punishment that causes females to be more cooperative. While the proof is missing, a previous study by Bshary and Grutter [20] showed that aggression by clients is punishment as it causes cleaners to feed more against their preference. Hence it is likely that male aggression has a similar effect. In other words, the threat of ‘punishment’ from males, which are larger and thus presumably have more capacity to punish, may act to reduce the benefit of cheating and thus shifts the females’ optimal foraging strategy. Bshary et al. [5] have therefore suggested that dominance interactions that facilitate punishment within paired members of the same species of cleaner fish may favour cooperation both between themselves and towards their clients. Their study
highlights the general finding that cooperation can be encouraged both through increased rewards for cooperating or through increased costs for not-cooperating. The latter may be the more common evolutionary outcome because the cost of punishing declines as it becomes more common, whereas the cost of rewarding cooperators increases as the trait becomes more common [10,11]. References 1. Hamilton, W.D. (1963). Evolution of altruistic behavior. Am. Nat. 97, 354–356. 2. Hamilton, W.D. (1964). Genetical evolution of social behaviour. J. Theor. Biol. 7, 1–52. 3. Axelrod, R., and Hamilton, W.D. (1981). The evolution of cooperation. Science 211, 1390–1396. 4. Hardin, G. (1968). Tragedy of commons. Science 162, 1243–1248. 5. Bshary, R., Grutter, A.S., Willener, A.S.T., and Leimar, O. (2008). Pairs of cooperating cleaner fish provide better service quality than singletons. Nature 455, 964–966. 6. West, S.A., Griffin, A.S., and Gardner, A. (2007). Evolutionary explanations for cooperation. Curr. Biol. 17, R661–R672. 7. Kokko, H., Johnstone, R.A., and CluttonBrock, T.H. (2001). The evolution of cooperative breeding through group augmentation. Proc. R. Soc. Lond. B 268, 187–196. 8. Foster, K.R., and Ratnieks, F.L.W. (2000). Social insects - facultative worker policing in a wasp. Nature 407, 692–693. 9. Cluttonbrock, T.H., and Parker, G.A. (1995). Punishment in animal societies. Nature 373, 209–216. 10. Gardner, A., and West, S.A. (2004). Cooperation and punishment, especially in humans. Am. Nat. 164, 753–764.
Electrical Synapses: Rectification Demystified Some electrical synapses rectify — they pass current preferentially in one direction. A new study argues that rectifying junctions result when the two sides of the junction contribute hemichannels with different properties to the gap junction. Eve Marder In 1959, Furshpan and Potter [1] published a landmark paper demonstrating the existence of electrical coupling between neurons in the escape system of crayfish. This paper came soon after the introduction of microelectrodes for intracellular recordings, and is often remembered as one of the earliest comprehensive studies of electrical coupling among neurons. What is often forgotten is that the junction studied by Furshpan and
Potter [1] shows rectification: that is, positive current flows preferentially in one direction, as illustrated in the simple schematic in Figure 1. What this means is that, despite the direct coupling between two neurons, information flow can nonetheless be more or less unidirectional. While some of the computational consequences of rectifying electrical junctions have been recognized [2,3], the mechanisms giving rise to rectification at electrical synapses were largely mysterious until the recent
11. Lehmann, L., Rousset, F., Roze, D., and Keller, L. (2007). Strong reciprocity or strong ferocity? A population genetic view of the evolution of altruistic punishment. Am. Nat. 170, 21–36. 12. Kiers, E.T., Rousseau, R.A., West, S.A., and Denison, R.F. (2003). Host sanctions and the legume-rhizobium mutualism. Nature 425, 78–81. 13. Trivers, R.L. (1971). Evolution of reciprocal altruism. Q. Rev. Biol. 46, 35–57. 14. Alexander, R.D. (1987). The Biology of Moral Systems (New York: Aldine de Gruyter). 15. Bshary, R., and Noe¨, R. (2003). Biological markets: the ubiquitous influence of partner choice on the dynamics of cleaner fish-client reef fish interactions. In Genetic and Cultural Evolution of Cooperation, P. Hammerstein, ed. (Cambridge, Mass., London: MIT Press in cooperation with Dahlem University Press), pp. 167–184. 16. Noe, R., and Hammerstein, P. (1994). Biological markets - supply-and-demand determine the effect of partner choice in cooperation, mutualism and mating. Behav. Ecol. Sociobiol. 35, 1–11. 17. Bshary, R., and Grutter, A.S. (2006). Image scoring and cooperation in a cleaner fish mutualism. Nature 441, 975–978. 18. Bshary, R., and Schaffer, D. (2002). Choosy reef fish select cleaner fish that provide high-quality service. Anim. Behav. 63, 557–564. 19. Charnov, E.L. (1976). Optimal foraging, marginal value theorem. Theor. Pop. Biol. 9, 129–136. 20. Bshary, R., and Grutter, A.S. (2005). Punishment and partner switching cause cooperative behaviour in a cleaning mutualism. Biol. Lett. 1, 396–399.
Institute of Cognitive and Evolutionary Anthropology, University of Oxford, Oxford OX2 6PN, UK. E-mail: [email protected]
DOI: 10.1016/j.cub.2008.11.018
paper in Current Biology by Phelan et al. [4]. Electrical synapses are formed by connexins in vertebrates [5] and innexins in invertebrates [6,7], with subunits contributed to the gap junctions from both cells. Therefore, it is expected that, when gap junctions couple cells of the same type, the proteins that form the pore connecting the two cells will be molecularly identical subunits of the appropriate innexins or connexins. In this case, one would predict that current should pass symmetrically between the two cells. In many cases in the nervous system, however, electrical synapses are found between neurons that are not of the same type [8,9]. For example, the classic studies of Furshpan and Potter [1] examined the properties of the rectifying junction between the lateral giant fiber and the motor giant neuron, and Phelan et al. [4] employed the escape circuit of Drosophila in which
Dispatch R35
VA
VB IB
IA B
A
IA
IB
VA
VA
VB
VB
IA
IB
VA
VA
VB
VB Current Biology
Figure 1. Cartoon schematic of two cells coupled by a rectifying electrical junction. Left: depolarizing current (I) injected into cell A depolarizes cell A (voltage VA) and to a lesser degree, cell B (VB). On the other hand, hyperpolarization of cell A has little effect on the VB. This indicates that depolarizing current passes preferentially from cell A to cell B. This is verified by current injections into cell B, that show that depolarization of cell B has little effect on the voltage in cell A, but hyperpolarization of cell B effectively hyperpolarizes cell A. (Thanks to Marie Goeritz for help with preparing this figure.)
the giant fibers connect with several classes of postsynaptic neurons. Because rectification is often seen at electrical junctions between neurons of different classes, this suggests that rectification could be associated with heteromeric gap junction channels [7,9], in which different subunits of the gap junction proteins might be contributed by the coupled neurons, and this is the conclusion of the new study by Phelan et al. [4]. In Drosophila, the shaking-B (shakB) innexin gene produces several transcripts that are translated into three different proteins: ShakB(N), ShakB(N+16) and ShakB(L). Mutations
in this gene disrupt electrical and dye coupling. Phelan et al. [4] attempted to rescue functions of the escape system by carrying out cell-specific expression of individual transcripts of the shakB gene. The result of these manipulations suggest that the synapses between the giant fibers and giant commissural interneurons are homotypic gap junctions formed from ShakB(N+16). In contrast, synapses between the giant fiber and several other neurons are likely to be formed from heterotypic junctions in which ShakB(N+16) hemichannels interact with ShakB(L) hemichannels. The actual demonstration that heteromeric channels formed by ShakB(N+16) and ShakB(L) produce rectifying junctions comes from experiments in which the shakB(n+16) and shakB(L)transcripts were injected into connexin-depleted Xenopus oocytes. Dual voltage clamp recordings were done to measure directly the properties of the gap junction conductance between oocytes. Oocyte pairs in which the two sides of the junction received different transcripts showed junctional conductances that were sharply rectifying, while oocyte pairs in which the two sides of the junction received the same transcript showed junctions that passed current symmetrically. Electrical junctions in other invertebrate ganglia show a wide range of rectification, from small, to moderate, to extensive [9,10]. Because it is highly likely that many neurons may express multiple transcripts derived from one or several innexin genes [7], this suggests that individual neurons might be able to contribute different classes of hemichannel subunits to a given junction, or to junctions with different target neurons [7]. Consequently, the final biophysical properties of a given electrical synapse could depend on how many of which
forms of innexin are contributed by each of the participating neurons. Finally, it is therefore easy to imagine that regulation of the expression of these genes could allow the extent of rectification to depend on developmental influences or the neuromodulatory environment. As varying the extent of rectification also alters the extent to which information flow in networks is bidirectional or unidirectional, modifications of the subunit composition to a gap junction could easily alter how neuronal circuits respond dynamically to their inputs. References 1. Furshpan, E.J., and Potter, D.D. (1959). Transmission at the giant motor synapses of the crayfish. J. Physiol. 145, 289–325. 2. Edwards, D.H., Yeh, S.R., and Krasne, F.B. (1998). Neuronal coincidence detection by voltage-sensitive electrical synapses. Proc. Natl. Acad. Sci. USA 95, 7145–7150. 3. Marder, E. (1998). Electrical synapses: beyond speed and synchrony to computation. Curr. Biol. 8, R795–R797. 4. Phelan, P., Goulding, L.A., Tam, J.L.Y., Allen, M.J., Dawber, R.J., Davies, J.A., and Bacon, J.P. (2008). Molecular mechanism of rectification at identified electrical synapses in the Drosophila giant fibre system. Curr. Biol. 18, 1955–1960. 5. Connors, B.W., and Long, M.A. (2004). Electrical synapses in the mammalian brain. Annu. Rev. Neurosci. 27, 393–418. 6. Phelan, P., Bacon, J.P., Davies, J.A., Stebbings, L.A., Todman, M.G., Avery, L., Baines, R.A., Barnes, T.M., Ford, C., Hekimi, S., et al. (1998). Innexins: a family of invertebrate gap-junction proteins. Trends Genet. 14, 348–349. 7. Phelan, P., and Starich, T.A. (2001). Innexins get into the gap. Bioessays 23, 388–396. 8. Marder, E. (1984). Roles for electrical coupling in neural circuits as revealed by selective neuronal deletions. J. Exp. Biol. 112, 147–167. 9. Kristan, W.B., Jr., Calabrese, R.L., and Friesen, W.O. (2005). Neuronal control of leech behavior. Prog. Neurobiol. 76, 279–327. 10. Johnson, B.R., Peck, J.H., and HarrisWarrick, R.M. (1993). Amine modulation of electrical coupling in the pyloric network of the lobster stomatogastric ganglion. J. Comp. Physiol. A 172, 715–732.
Volen Center and Biology Department MS013, Brandeis University, Waltham, MA 02454, USA. E-mail: [email protected] DOI: 10.1016/j.cub.2008.11.008
the food being withdrawn, confirmed these findings and again revealed that the feeding choices of females were conditional upon whether they were feeding alone or in a pair. Why are females conditionally cooperative whereas males are not so inclined? Interestingly the males were observed to behave aggressively towards the females quite often after removal of the food or when the client left. This aggressive behaviour could be an evolved mechanism of punishment that causes females to be more cooperative. While the proof is missing, a previous study by Bshary and Grutter [20] showed that aggression by clients is punishment as it causes cleaners to feed more against their preference. Hence it is likely that male aggression has a similar effect. In other words, the threat of ‘punishment’ from males, which are larger and thus presumably have more capacity to punish, may act to reduce the benefit of cheating and thus shifts the females’ optimal foraging strategy. Bshary et al. [5] have therefore suggested that dominance interactions that facilitate punishment within paired members of the same species of cleaner fish may favour cooperation both between themselves and towards their clients. Their study
highlights the general finding that cooperation can be encouraged both through increased rewards for cooperating or through increased costs for not-cooperating. The latter may be the more common evolutionary outcome because the cost of punishing declines as it becomes more common, whereas the cost of rewarding cooperators increases as the trait becomes more common [10,11]. References 1. Hamilton, W.D. (1963). Evolution of altruistic behavior. Am. Nat. 97, 354–356. 2. Hamilton, W.D. (1964). Genetical evolution of social behaviour. J. Theor. Biol. 7, 1–52. 3. Axelrod, R., and Hamilton, W.D. (1981). The evolution of cooperation. Science 211, 1390–1396. 4. Hardin, G. (1968). Tragedy of commons. Science 162, 1243–1248. 5. Bshary, R., Grutter, A.S., Willener, A.S.T., and Leimar, O. (2008). Pairs of cooperating cleaner fish provide better service quality than singletons. Nature 455, 964–966. 6. West, S.A., Griffin, A.S., and Gardner, A. (2007). Evolutionary explanations for cooperation. Curr. Biol. 17, R661–R672. 7. Kokko, H., Johnstone, R.A., and CluttonBrock, T.H. (2001). The evolution of cooperative breeding through group augmentation. Proc. R. Soc. Lond. B 268, 187–196. 8. Foster, K.R., and Ratnieks, F.L.W. (2000). Social insects - facultative worker policing in a wasp. Nature 407, 692–693. 9. Cluttonbrock, T.H., and Parker, G.A. (1995). Punishment in animal societies. Nature 373, 209–216. 10. Gardner, A., and West, S.A. (2004). Cooperation and punishment, especially in humans. Am. Nat. 164, 753–764.
Electrical Synapses: Rectification Demystified Some electrical synapses rectify — they pass current preferentially in one direction. A new study argues that rectifying junctions result when the two sides of the junction contribute hemichannels with different properties to the gap junction. Eve Marder In 1959, Furshpan and Potter [1] published a landmark paper demonstrating the existence of electrical coupling between neurons in the escape system of crayfish. This paper came soon after the introduction of microelectrodes for intracellular recordings, and is often remembered as one of the earliest comprehensive studies of electrical coupling among neurons. What is often forgotten is that the junction studied by Furshpan and
Potter [1] shows rectification: that is, positive current flows preferentially in one direction, as illustrated in the simple schematic in Figure 1. What this means is that, despite the direct coupling between two neurons, information flow can nonetheless be more or less unidirectional. While some of the computational consequences of rectifying electrical junctions have been recognized [2,3], the mechanisms giving rise to rectification at electrical synapses were largely mysterious until the recent
11. Lehmann, L., Rousset, F., Roze, D., and Keller, L. (2007). Strong reciprocity or strong ferocity? A population genetic view of the evolution of altruistic punishment. Am. Nat. 170, 21–36. 12. Kiers, E.T., Rousseau, R.A., West, S.A., and Denison, R.F. (2003). Host sanctions and the legume-rhizobium mutualism. Nature 425, 78–81. 13. Trivers, R.L. (1971). Evolution of reciprocal altruism. Q. Rev. Biol. 46, 35–57. 14. Alexander, R.D. (1987). The Biology of Moral Systems (New York: Aldine de Gruyter). 15. Bshary, R., and Noe¨, R. (2003). Biological markets: the ubiquitous influence of partner choice on the dynamics of cleaner fish-client reef fish interactions. In Genetic and Cultural Evolution of Cooperation, P. Hammerstein, ed. (Cambridge, Mass., London: MIT Press in cooperation with Dahlem University Press), pp. 167–184. 16. Noe, R., and Hammerstein, P. (1994). Biological markets - supply-and-demand determine the effect of partner choice in cooperation, mutualism and mating. Behav. Ecol. Sociobiol. 35, 1–11. 17. Bshary, R., and Grutter, A.S. (2006). Image scoring and cooperation in a cleaner fish mutualism. Nature 441, 975–978. 18. Bshary, R., and Schaffer, D. (2002). Choosy reef fish select cleaner fish that provide high-quality service. Anim. Behav. 63, 557–564. 19. Charnov, E.L. (1976). Optimal foraging, marginal value theorem. Theor. Pop. Biol. 9, 129–136. 20. Bshary, R., and Grutter, A.S. (2005). Punishment and partner switching cause cooperative behaviour in a cleaning mutualism. Biol. Lett. 1, 396–399.
Institute of Cognitive and Evolutionary Anthropology, University of Oxford, Oxford OX2 6PN, UK. E-mail: [email protected]
DOI: 10.1016/j.cub.2008.11.018
paper in Current Biology by Phelan et al. [4]. Electrical synapses are formed by connexins in vertebrates [5] and innexins in invertebrates [6,7], with subunits contributed to the gap junctions from both cells. Therefore, it is expected that, when gap junctions couple cells of the same type, the proteins that form the pore connecting the two cells will be molecularly identical subunits of the appropriate innexins or connexins. In this case, one would predict that current should pass symmetrically between the two cells. In many cases in the nervous system, however, electrical synapses are found between neurons that are not of the same type [8,9]. For example, the classic studies of Furshpan and Potter [1] examined the properties of the rectifying junction between the lateral giant fiber and the motor giant neuron, and Phelan et al. [4] employed the escape circuit of Drosophila in which
Dispatch R35
VA
VB IB
IA B
A
IA
IB
VA
VA
VB
VB
IA
IB
VA
VA
VB
VB Current Biology
Figure 1. Cartoon schematic of two cells coupled by a rectifying electrical junction. Left: depolarizing current (I) injected into cell A depolarizes cell A (voltage VA) and to a lesser degree, cell B (VB). On the other hand, hyperpolarization of cell A has little effect on the VB. This indicates that depolarizing current passes preferentially from cell A to cell B. This is verified by current injections into cell B, that show that depolarization of cell B has little effect on the voltage in cell A, but hyperpolarization of cell B effectively hyperpolarizes cell A. (Thanks to Marie Goeritz for help with preparing this figure.)
the giant fibers connect with several classes of postsynaptic neurons. Because rectification is often seen at electrical junctions between neurons of different classes, this suggests that rectification could be associated with heteromeric gap junction channels [7,9], in which different subunits of the gap junction proteins might be contributed by the coupled neurons, and this is the conclusion of the new study by Phelan et al. [4]. In Drosophila, the shaking-B (shakB) innexin gene produces several transcripts that are translated into three different proteins: ShakB(N), ShakB(N+16) and ShakB(L). Mutations
in this gene disrupt electrical and dye coupling. Phelan et al. [4] attempted to rescue functions of the escape system by carrying out cell-specific expression of individual transcripts of the shakB gene. The result of these manipulations suggest that the synapses between the giant fibers and giant commissural interneurons are homotypic gap junctions formed from ShakB(N+16). In contrast, synapses between the giant fiber and several other neurons are likely to be formed from heterotypic junctions in which ShakB(N+16) hemichannels interact with ShakB(L) hemichannels. The actual demonstration that heteromeric channels formed by ShakB(N+16) and ShakB(L) produce rectifying junctions comes from experiments in which the shakB(n+16) and shakB(L)transcripts were injected into connexin-depleted Xenopus oocytes. Dual voltage clamp recordings were done to measure directly the properties of the gap junction conductance between oocytes. Oocyte pairs in which the two sides of the junction received different transcripts showed junctional conductances that were sharply rectifying, while oocyte pairs in which the two sides of the junction received the same transcript showed junctions that passed current symmetrically. Electrical junctions in other invertebrate ganglia show a wide range of rectification, from small, to moderate, to extensive [9,10]. Because it is highly likely that many neurons may express multiple transcripts derived from one or several innexin genes [7], this suggests that individual neurons might be able to contribute different classes of hemichannel subunits to a given junction, or to junctions with different target neurons [7]. Consequently, the final biophysical properties of a given electrical synapse could depend on how many of which
forms of innexin are contributed by each of the participating neurons. Finally, it is therefore easy to imagine that regulation of the expression of these genes could allow the extent of rectification to depend on developmental influences or the neuromodulatory environment. As varying the extent of rectification also alters the extent to which information flow in networks is bidirectional or unidirectional, modifications of the subunit composition to a gap junction could easily alter how neuronal circuits respond dynamically to their inputs. References 1. Furshpan, E.J., and Potter, D.D. (1959). Transmission at the giant motor synapses of the crayfish. J. Physiol. 145, 289–325. 2. Edwards, D.H., Yeh, S.R., and Krasne, F.B. (1998). Neuronal coincidence detection by voltage-sensitive electrical synapses. Proc. Natl. Acad. Sci. USA 95, 7145–7150. 3. Marder, E. (1998). Electrical synapses: beyond speed and synchrony to computation. Curr. Biol. 8, R795–R797. 4. Phelan, P., Goulding, L.A., Tam, J.L.Y., Allen, M.J., Dawber, R.J., Davies, J.A., and Bacon, J.P. (2008). Molecular mechanism of rectification at identified electrical synapses in the Drosophila giant fibre system. Curr. Biol. 18, 1955–1960. 5. Connors, B.W., and Long, M.A. (2004). Electrical synapses in the mammalian brain. Annu. Rev. Neurosci. 27, 393–418. 6. Phelan, P., Bacon, J.P., Davies, J.A., Stebbings, L.A., Todman, M.G., Avery, L., Baines, R.A., Barnes, T.M., Ford, C., Hekimi, S., et al. (1998). Innexins: a family of invertebrate gap-junction proteins. Trends Genet. 14, 348–349. 7. Phelan, P., and Starich, T.A. (2001). Innexins get into the gap. Bioessays 23, 388–396. 8. Marder, E. (1984). Roles for electrical coupling in neural circuits as revealed by selective neuronal deletions. J. Exp. Biol. 112, 147–167. 9. Kristan, W.B., Jr., Calabrese, R.L., and Friesen, W.O. (2005). Neuronal control of leech behavior. Prog. Neurobiol. 76, 279–327. 10. Johnson, B.R., Peck, J.H., and HarrisWarrick, R.M. (1993). Amine modulation of electrical coupling in the pyloric network of the lobster stomatogastric ganglion. J. Comp. Physiol. A 172, 715–732.
Volen Center and Biology Department MS013, Brandeis University, Waltham, MA 02454, USA. E-mail: [email protected] DOI: 10.1016/j.cub.2008.11.008