- Email: [email protected]
Neurobiology: All Synapses Are Created Equal
Current Biology Vol 25 No 1 R38
References
Figure 1. Moral judgment. Tympanum of the Last Judgment, at the central portal of Notre-Dame de Paris. Photo: Wikimedia Commons, Philippe Ale`s.
motivation and reward systems. Specifically, increased affluence generally prompts a shift away from ‘fast life’ strategies focused on resource acquisition and competition and instead encourages a move toward ‘slow life’ strategies, such as self-control techniques and cooperation. Thus, as societal security and standards of living improved just prior the Axial Age, short-term materialistic goals (such as resource attainment and coercive interactions) may have been systematically de-prioritized in favor of long term-goals (such as self-development and cooperation). In turn, this motivational shift may have favored the spread of new religious doctrines consistent with these long-term strategies — for instance, philosophies that touted the importance of self-discipline and compassion for others. The findings of Baumard et al. [3] and their explanation will prove controversial. Their theory differs sharply from other accounts of the rise of moralizing religions, including the view that such religions evolved and spread because they help promote large-scale cooperation in large societies — individuals are nicer to one another if they believe in moralizing deities [4,11,12]. And their findings are not easy to reconcile with those of other large-scale empirical studies. A paper just published by Botero et al. [13] finds, based on analyses of 583 societies, that ‘‘belief[s] in moralizing high gods . are more prevalent among societies that inhabit poorer environments and are prone to ecological duress.’’ While not directly incompatible with the findings
of Baumard et al. [3], the results of Botero and colleagues seem to push in the opposite theoretical direction, as they suggest that moralizing religions emerge as a response to stress, not security. Furthermore, in the world we live in now, the most affluent countries are the least religious, not the most [1,14]. Perhaps the relationship between money and moralizing religions takes the shape of an inverted-U: some threshold of affluence has to be passed for moralizing religions to emerge, but further affluence leads to secularization, at least in the 21st century. These issues, and many others, remain open. But the theoretical ingenuity and methodological richness of studies such as those reported by Baumard and his colleagues nicely illustrate how science can make progress in the study of the origin of religion.
1. Pew Research Center. (2014). Worldwide, many see belief in god as essential to morality, March, 2014. Retrieved from http://www. pewglobal.org/2014/03/13/worldwide-manysee-belief-in-god-as-essential-to-morality/2/. 2. Dostoevsky, F. (1970). The Brothers Karamazov, First Bantam Edition (New York: Bantam Books), (Original work published 1880). 3. Baumard, N., Hyafil, A., Morris, I., and Boyer, P. (2015). Increased affluence explains the emergence of ascetic wisdoms and moralizing religions. Curr. Biol. 25, 10–15. 4. Norenzayan, A. (2013). Big Gods: How Religion Transformed Cooperation and Conflict (Princeton, NJ: Princeton University Press). 5. Baumard, N., and Boyer, P. (2013). Explaining moral religions. Trends Cogn. Sci. 17, 272–280. 6. Burkert, W.R.J. (1985). Greek Religion: Archaic and Classical (Oxford: Blackwell Publishing Ltd.). 7. Kramer, S.N. (1961). Mythologies of the Ancient World, First Edition (Garden City, NY: Doubleday). 8. Wright, R. (2009). The Evolution of God (New York: Little, Brown and Company). 9. Jaspers, K. (1953). The Origin and Goal of History (Vom Ursprung und Ziel der Geschichte, translated into English) (New Haven, CT: Yale University Press). 10. Morris, I. (2013). The Measure of Civilization: How Social Development Decides the Fate of Nations (Princeton, NJ: Princeton University Press). 11. Norenzayan, A., and Shariff, A.F. (2008). The origin and evolution of religious prosociality. Science 322, 58–62. 12. Shariff, A., Norenzayan, A., and Henrich, J. (2010). The birth of high gods. In Evolution, Culture, and the Human Mind, M. Schaller, A. Norenzayan, S.J. Heine, T. Yamagishi, and T. Kameda, eds. (New York: Psychology PressTaylor & Francis Group), pp. 119–136. 13. Botero, C.A., Gardner, B., Kirby, K.R., Bulbulia, J., Gavin, M.C., and Gray, R.D. (2014). The ecology of religious beliefs. Proc. Natl. Acad. Sci. USA 111, 16784–16789. 14. Pew Research Center. (2008). The Pew global attitudes project: Unfavorable views of Jews and Muslims on the increase in Europe, September 2008. Retrieved from http://www. pewglobal.org/2008/09/17/unfavorable-viewsof-jews-and-muslims-on-the-increase-ineurope/.
Department of Psychology, Yale University, 2 Hillhouse Avenue, New Haven, CT 06511, USA. *E-mail: [email protected] http://dx.doi.org/10.1016/j.cub.2014.11.042
Neurobiology: All Synapses Are Created Equal There are two main modalities of communication between neurons, known as electrical and chemical synaptic transmission. Despite striking differences in their underlying mechanisms, new evidence suggests that the formation of electrically and chemically mediated synapses is under common regulatory processes. Alberto E. Pereda Brain cells communicate through macromolecular complexes that make possible the exchange of information
between neighboring neurons. These anatomical and functional specializations are called ‘synapses’ (the Greek word used by Foster and Sherrington, which means an active,
Dispatch R39
sought process of contact) [1] and their precise distribution within nervous systems delineates networks of functionally interconnected neurons. We recognize two main modalities of synaptic communication, chemical and electrical, with fundamentally different underlying mechanisms (Figure 1). At chemical synapses, one of the neurons releases a molecule that after traveling through the extracellular space binds to specific receptors located in a second neuron, thus initiating diverse cellular processes that range from transient modifications of the membrane resting potential to changes in gene expression. In contrast, electrically mediated synapses rely on structures known as gap junctions, which are clusters of intercellular channels that provide conduits for the diffusion of signaling molecules and a pathway of low resistance for the spread of electrical currents, a form of signaling characteristic of brain cells. Given the radical differences in the strategy of communication and the involved molecules, it is generally perceived that these two forms of communication operate independently. However, there is a growing body of evidence indicating that these two forms of transmission rather extensively interact, both during brain development and in adulthood (for review see [2]), and a new study by Miller et al. [3] reported in this issue of Current Biology now shows that the formation of electrical and chemical synapses during development requires common regulatory steps. Synaptic transmission is a complex cellular function that requires the interaction of multiple proteins. Neurobeachin is a multidomain scaffolding protein identified during screens for novel synaptic proteins that was found to be essential for synaptic transmission [4,5]. This protein is believed to be involved in neuronal post-Golgi membrane trafficking and it was found associated with pleomorphic tubulovesicular endomembranes at the trans side of the Golgi apparatus and at the postsynaptic membrane in some synapses [4]. Analysis of mice lacking Neurobeachin indicated a clear synaptic function for this protein. Consistent with its requirement for neuromuscular transmission [6], Neurobeachin null-mutant mice are paralyzed and die at perinatal ages
Electrical synapse
Chemical synapse
Presynaptic neuron Ca++
Postsynaptic neuron
Neurobeachin
Current Biology
Figure 1. Neurobeachin regulates the formation of chemical and electrical synapses. The cartoon summarizes major differences between the mechanisms of chemical (left) and electrical (right) synaptic transmission. Yellow dashed areas represent protein scaffolds associated with neurotransmitter receptors (left) and gap junction channels (right). Neurobeachin is required only at the postsynaptic neuron for the formation of both chemical and electrical synapses.
[5,7]. These animals also exhibited reduced synaptic responses at central synapses and a reduction in the surface expression of glutamate (excitatory) and GABA (inhibitory) receptors, which seem to accumulate in the biosynthetic pathway [8]. While the direct association of Neurobeachin to scaffolding proteins involved in trafficking of glutamate receptors during synaptogenesis has been established [8], the reduction in surface expression of GABA receptors (whose trafficking involves a different set of scaffolding proteins) suggests that this complex multidomain protein is capable of acting as a scaffold for binding a wide range of proteins. Thus, both excitatory and inhibitory chemical synapses require
Neurobeachin for their formation and proper function. The paper by Miller et al. provides conclusive evidence indicating that Neurobeachin is also required for the formation of gap junction-mediated electrical synapses. Combining the power of zebrafish forward genetics and the analytical advantages of identifiable synapses participating in a well-established neuronal network such as the Mauther cell escape system [9], the paper elegantly demonstrates that mutant zebrafish lacking Neurobeachin show a deficit in the formation of glycinergic synapses and, surprisingly, of electrical synapses. Gap junction channels have been shown to actively traffic at rates that are comparable to those of
Current Biology Vol 25 No 1 R40
glutamate receptors [10,11] including at Mauthner cell electrical synapses where it was proposed it might underlie regulation of the synaptic strength [11]. In analogy to chemical synapses, Neurobeachin could influence electrical transmission by regulating the traffic of gap junction channels via interactions with scaffolding proteins that are specific for this modality of communication. From a more general point of view, the results indicate that all forms of synaptic communication, regardless of sign (excitatory or inhibitory), molecular composition or ultimate mechanism of transmission, share common developmental steps, revealing an unexpected unity of interneuronal communication. Such unity is further emphasized by recent findings in the Drosophila escape network where the formation of electrical and chemical synapses was found to be co-regulated by the transcription factor Engrailed [12], suggesting that invertebrates and vertebrates share common strategies of interneuronal communication. The second surprising finding was that Neurobeachin is only required postsynaptically for the formation of both chemical and electrical synapses. Chimera analysis in zebrafish demonstrated that Neurobeachin was necessary only when expressed postsynaptically. In contrast to chemical synapses that have a distinct asymmetry in the molecular composition of pre- and postsynaptic sites (specialized in transmitter and receptor clustering, respectively), gap junctions are perceived as symmetric structures, as a single intercellular gap junction channel is formed by the apposition of two hemichannels contributed by each of the coupled cells (Figure 1). Recent data indicate that vertebrate electrical synapses (as some in invertebrates) can be molecularly asymmetric when the contributing hemichannels are formed by different gap junction channel-forming proteins [13]. The results by Miller et al. suggest that Neurobeachin has an important postsynaptic function at electrical synapses. Gap junctions are currently considered part of large macromolecular complexes that contain, in addition to the channel-forming proteins or ‘connexins’, a number of associated proteins that support their function [14]. The detailed composition of this
scaffold at electrical synapses is currently unknown and it could potentially be as complex as that of postsynaptic densities at glutamatergic synapses [15]. Given its established role as a scaffolding protein in membrane trafficking, Neurobeachin could participate or closely interact with proteins that form this complex. Because Neurobeachin was found to be required only postsynaptically, the results of Millet et al. suggest that differences in the molecular composition of electrical synapses might not be restricted to the intercellular channel itself [13] but could also include asymmetries in the molecular composition of the scaffold that regulates the function of these channels. Interestingly, Neurobeachin has recently been identified as a candidate gene for autism [16] and heterozygous mice lacking one copy of the Neurobeachin gene were reported to have behavioral deficits that are reminiscent of symptoms observed in autistic patients [17]. Considered by some as a disorder of early synaptic development [18] the results reported by Miller et al. suggest that electrical synapses could contribute, together with alterations in chemical transmission [17], to the pathological processes underlying autism spectrum disorders. Consistent with this possibility, it was suggested that brain desynchronization could contribute to autism [19]. Disruption of electrical synapses formed by the gap junction-forming protein connexin 36 in the inferior olive (a brainstem structure involved in fine motor control that heavily relies in electrical synapses) might impede the synchronization required for the development of various motor acts, including the acquisition of normal language skills [19]. Electrical synapses are known to promote coordinated neuronal activity and are primarily formed by connexin 36, which is widely expressed in mammalian brain [20]. Electrical and chemical synapses closely interact during brain development and early disruption of electrical synapse formation can lead to defects in the formation of chemical synapses (for review see [2]). In this way, a reduction in the formation of electrical synapses would lead not only to decreased synchronization of neuronal activity but also to deficits in the formation of chemical synapses, resulting in defects and subsequent
dysfunction of critical neural networks. Because electrical synapses in the Mauthner cell network are formed by fish homologs of connexin 36 [13], the data reported in Miller et al. have important pathological implications and opens a new avenue of investigation of the mechanisms underlying autism spectrum disorders. Thus, altogether the results suggest that, rather than electrical or chemical, synaptic communication should be considered a single entity, which is electrical and chemical, and that information within neural networks is simultaneously communicated by combining these two complementary modalities of synaptic transmission. References 1. Tansey, E.M. (1997). Not committing barbarisms: Sherrington and the synapse, 1897. Brain Res. Bull. 44, 211–212. 2. Pereda, A.E. (2014). Electrical synapses and their functional interactions with chemical synapses. Nat. Rev. Neurosci. 15, 250–263. 3. Miller, A.C., Voelker, L.H., Shah, A.N., and Moens, C.B. (2015). Neurobeachin is required postsynaptically for electrical and chemical synapse formation. Curr. Biol. 25, 16–28. 4. Wang, X., Herberg, F.W., Laue, M.M., Wullner, C., Hu, B., Petrasch-Parwez, E., and Kilimann, M.W. (2000). Neurobeachin: A protein kinase A-anchoring, beige/ Chediak-higashi protein homolog implicated in neuronal membrane traffic. J. Neurosci. 20, 8551–8565. 5. Nair, R., Lauks, J., Jung, S., Cooke, N.E., de Wit, H., Brose, N., Kilimann, M.W., Verhage, M., and Rhee, J. (2013). Neurobeachin regulates neurotransmitter receptor trafficking to synapses. J. Cell Biol. 200, 61–80. 6. Su, Y., Balice-Gordon, R.J., Hess, D.M., Landsman, D.S., Minarcik, J., Golden, J., Hurwitz, I., Liebhaber, S.A., and Cooke, N.E. (2004). Neurobeachin is essential for neuromuscular synaptic transmission. J. Neurosci. 24, 3627–3636. 7. Medrihan, L., Rohlmann, A., Fairless, R., Andrae, J., Do¨ring, M., Missler, M., Zhang, W., and Kilimann, M.W. (2009). Neurobeachin, a protein implicated in membrane protein traffic and autism, is required for the formation and functioning of central synapses. J. Physiol. 587, 5095–5106. 8. Lauks, J., Klemmer, P., Farzana, F., Karupothula, R., Zalm, R., Cooke, N.E., Li, K.W., Smit, A.B., Toonen, R., and Verhage, M. (2012). Synapse associated protein 102 (SAP102) binds the C-terminal part of the scaffolding protein neurobeachin. PLoS One 7, e39420. 9. Korn, H., and Faber, D.S. (2005). The Mauthner cell half a century later: a neurobiological model for decision-making? Neuron 47, 13–28. 10. Laird, D.W. (1996). The life cycle of a connexin: gap junction formation, removal, and degradation. J. Bioenerg. Biomembr. 28, 311–318. 11. Flores, C.E., Nannapaneni, S., Davidson, K.G.V., Yasumura, T., Bennett, M.V.L., Rash, J.E., and Pereda, A.E. (2012). Trafficking of gap junction channels at a vertebrate electrical synapse in vivo. Proc. Natl. Acad. Sci. USA 109, E573–E582. 12. Pe´zier, A., Jezzini, S.H., Marie, B., and Blagburn, J.M. (2014). Engrailed alters the specificity of synaptic connections of Drosophila auditory neurons with the giant fiber. J. Neurosci. 34, 11691–11704. 13. Rash, J.E., Curti, S., Vanderpool, K.G., Kamasawa, N., Nannapaneni, S., PalaciosPrado, N., Flores, C.E., Yasumura, T., O’Brien, J., Lynn, B.D., et al. (2013). Molecular
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and functional asymmetry at a vertebrate electrical synapse. Neuron 79, 957–969. 14. Herve´, J.-C., Bourmeyster, N., and Sarrouilhe, D. (2004). Diversity in protein-protein interactions of connexins: emerging roles. Biochim. Biophys. Acta 1662, 22–41. 15. Lynn, B.D., Li, X., and Nagy, J.I. (2012). Under construction: building the macromolecular superstructure and signaling components of an electrical synapse. J. Membr. Biol. 245, 303–317. 16. Volders, K., Nuytens, K., and Creemers, J.W.M. (2011). The autism candidate gene Neurobeachin encodes a scaffolding protein
implicated in membrane trafficking and signaling. Curr. Mol. Med. 11, 204–217. 17. Nuytens, K., Gantois, I., Stijnen, P., Iscru, E., Laeremans, A., Serneels, L., Van Eylen, L., Liebhaber, S.A., Devriendt, K., Balschun, D., et al. (2013). Haploinsufficiency of the autism candidate gene Neurobeachin induces autism-like behaviors and affects cellular and molecular processes of synaptic plasticity in mice. Neurobiol. Dis. 51, 144–151. 18. Zoghbi, H.Y. (2003). Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302, 826–830. 19. Welsh, J.P., Ahn, E.S., and Placantonakis, D.G. (2005). Is autism due to brain
Linguistics: Evolution and Language Change Linguists have long identified sound changes that occur in parallel. Now novel research shows how Bayesian modeling can capture complex concerted changes, revealing how evolution of sounds proceeds. Claire Bowern English speakers who study languages such as German, French, or Spanish are accustomed to coming across words that are similar to their English counterparts. For example, many words that start with p in English start with pf in German, such as plum – Pflaume, pan – Pfanne, penny – Pfennig, and so on. Sister languages show many such regularities, and this has formed the cornerstone for research on language change for nearly two centuries [1,2]. These regularities have allowed linguists to discover many of the processes of language evolution, and how language evolution may be similar to biological evolution. Now, in this issue of Current Biology, Hruschka and colleagues [3] have identified regular sound change as a process similar to concerted evolution in biology. They provide the first statistical model which allows us to study the properties of regular sound change systematically, as well as to compare it to concerted evolution. How Sound Change Works All languages have a set of distinctive sounds, called ‘phonemes’. These are abstract sound categories, which in combination make up words. The word pat, for example, has three phonemes (p, a, and t). The substitution of one phoneme for another changes the meaning of the word, or turns a word
into a non-word. For example, the difference between pat and cat is the first phoneme (p in the first case, k in the second). Phonemes are articulated in different ways. The realization phonemes change according to the position at which they occur in the word, the surrounding phonemes, and physiological traits of the speaker pronouncing the word. For example, the pronunciation of the /k/ phoneme in cat is different from the same phoneme in key. In the latter word, the front vowel pulls the tongue blade forward, leading to a more forward pronunciation. Aspiration is another example. Consider the difference between the t in pat and the t in tap. In the second case, the t has a puff of air (called ‘aspiration’) which is absent from the t in pat. However, no English speaker would consider that pat and tap don’t otherwise have the same phonemes. Finally, the distinctive realization of phonemes is what produces different accents. The distinction between phonemes and their realization is somewhat akin to the genotype–phenotype distinction in biology. The pronunciation of phonemes can change over time. This is called ‘sound change’. Within a language, individuals have different realizations of phonemes. These realizations are subject to selection pressures at both the individual and population level [4]. For example, some variants undergo positive selection and spread
desynchronization? Int. J. Dev. Neurosci. 23, 253–263. 20. Condorelli, D.F., Belluardo, N., TrovatoSalinaro, A., and Mudo`, G. (2000). Expression of Cx36 in mammalian neurons. Brain Res. Brain Res. Rev. 32, 72–85.
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA. E-mail: [email protected] http://dx.doi.org/10.1016/j.cub.2014.11.029
because they are easier to perceive. In our example of the different realizations of k above, for example, a fronted k before a front vowel enhances the cues for the following vowel. Other variants may be positively or negatively selected because they are associated with particular social groups [5]. Over time, these changes may lead to changes in the phonemes themselves. In my German example above, for example, p has become an affricate pf. Linguistics and Biology At this point, biologists will no doubt be thinking of numerous parallels between linguistic and biological evolution. Words are somewhat like genes: they are transmitted vertically, and the nucleotide or phoneme sequences they comprise can change individually or concertedly. There are many broad similarities between linguistic and biological evolution [4,6]; for example, both involve homologous units which descend from common ancestors, which allow us to trace the history of those descent patterns using evolutionary models. ‘Concerted change’ is central to historical linguistics. It was the regularities in correspondences which first allowed linguists to provide principled definitions of language relationships [7], by showing that such changes lead to systematic similarities which could not arise by chance. Sporadic, irregular changes do occur, but they are concentrated in certain sound sequences, or are the result of changes in word structure, or reflect loans from related languages. Though the parallels between linguistic and biological evolution have been discussed since Darwin [8,9], until the last ten years the two disciplines have used different
References
Figure 1. Moral judgment. Tympanum of the Last Judgment, at the central portal of Notre-Dame de Paris. Photo: Wikimedia Commons, Philippe Ale`s.
motivation and reward systems. Specifically, increased affluence generally prompts a shift away from ‘fast life’ strategies focused on resource acquisition and competition and instead encourages a move toward ‘slow life’ strategies, such as self-control techniques and cooperation. Thus, as societal security and standards of living improved just prior the Axial Age, short-term materialistic goals (such as resource attainment and coercive interactions) may have been systematically de-prioritized in favor of long term-goals (such as self-development and cooperation). In turn, this motivational shift may have favored the spread of new religious doctrines consistent with these long-term strategies — for instance, philosophies that touted the importance of self-discipline and compassion for others. The findings of Baumard et al. [3] and their explanation will prove controversial. Their theory differs sharply from other accounts of the rise of moralizing religions, including the view that such religions evolved and spread because they help promote large-scale cooperation in large societies — individuals are nicer to one another if they believe in moralizing deities [4,11,12]. And their findings are not easy to reconcile with those of other large-scale empirical studies. A paper just published by Botero et al. [13] finds, based on analyses of 583 societies, that ‘‘belief[s] in moralizing high gods . are more prevalent among societies that inhabit poorer environments and are prone to ecological duress.’’ While not directly incompatible with the findings
of Baumard et al. [3], the results of Botero and colleagues seem to push in the opposite theoretical direction, as they suggest that moralizing religions emerge as a response to stress, not security. Furthermore, in the world we live in now, the most affluent countries are the least religious, not the most [1,14]. Perhaps the relationship between money and moralizing religions takes the shape of an inverted-U: some threshold of affluence has to be passed for moralizing religions to emerge, but further affluence leads to secularization, at least in the 21st century. These issues, and many others, remain open. But the theoretical ingenuity and methodological richness of studies such as those reported by Baumard and his colleagues nicely illustrate how science can make progress in the study of the origin of religion.
1. Pew Research Center. (2014). Worldwide, many see belief in god as essential to morality, March, 2014. Retrieved from http://www. pewglobal.org/2014/03/13/worldwide-manysee-belief-in-god-as-essential-to-morality/2/. 2. Dostoevsky, F. (1970). The Brothers Karamazov, First Bantam Edition (New York: Bantam Books), (Original work published 1880). 3. Baumard, N., Hyafil, A., Morris, I., and Boyer, P. (2015). Increased affluence explains the emergence of ascetic wisdoms and moralizing religions. Curr. Biol. 25, 10–15. 4. Norenzayan, A. (2013). Big Gods: How Religion Transformed Cooperation and Conflict (Princeton, NJ: Princeton University Press). 5. Baumard, N., and Boyer, P. (2013). Explaining moral religions. Trends Cogn. Sci. 17, 272–280. 6. Burkert, W.R.J. (1985). Greek Religion: Archaic and Classical (Oxford: Blackwell Publishing Ltd.). 7. Kramer, S.N. (1961). Mythologies of the Ancient World, First Edition (Garden City, NY: Doubleday). 8. Wright, R. (2009). The Evolution of God (New York: Little, Brown and Company). 9. Jaspers, K. (1953). The Origin and Goal of History (Vom Ursprung und Ziel der Geschichte, translated into English) (New Haven, CT: Yale University Press). 10. Morris, I. (2013). The Measure of Civilization: How Social Development Decides the Fate of Nations (Princeton, NJ: Princeton University Press). 11. Norenzayan, A., and Shariff, A.F. (2008). The origin and evolution of religious prosociality. Science 322, 58–62. 12. Shariff, A., Norenzayan, A., and Henrich, J. (2010). The birth of high gods. In Evolution, Culture, and the Human Mind, M. Schaller, A. Norenzayan, S.J. Heine, T. Yamagishi, and T. Kameda, eds. (New York: Psychology PressTaylor & Francis Group), pp. 119–136. 13. Botero, C.A., Gardner, B., Kirby, K.R., Bulbulia, J., Gavin, M.C., and Gray, R.D. (2014). The ecology of religious beliefs. Proc. Natl. Acad. Sci. USA 111, 16784–16789. 14. Pew Research Center. (2008). The Pew global attitudes project: Unfavorable views of Jews and Muslims on the increase in Europe, September 2008. Retrieved from http://www. pewglobal.org/2008/09/17/unfavorable-viewsof-jews-and-muslims-on-the-increase-ineurope/.
Department of Psychology, Yale University, 2 Hillhouse Avenue, New Haven, CT 06511, USA. *E-mail: [email protected] http://dx.doi.org/10.1016/j.cub.2014.11.042
Neurobiology: All Synapses Are Created Equal There are two main modalities of communication between neurons, known as electrical and chemical synaptic transmission. Despite striking differences in their underlying mechanisms, new evidence suggests that the formation of electrically and chemically mediated synapses is under common regulatory processes. Alberto E. Pereda Brain cells communicate through macromolecular complexes that make possible the exchange of information
between neighboring neurons. These anatomical and functional specializations are called ‘synapses’ (the Greek word used by Foster and Sherrington, which means an active,
Dispatch R39
sought process of contact) [1] and their precise distribution within nervous systems delineates networks of functionally interconnected neurons. We recognize two main modalities of synaptic communication, chemical and electrical, with fundamentally different underlying mechanisms (Figure 1). At chemical synapses, one of the neurons releases a molecule that after traveling through the extracellular space binds to specific receptors located in a second neuron, thus initiating diverse cellular processes that range from transient modifications of the membrane resting potential to changes in gene expression. In contrast, electrically mediated synapses rely on structures known as gap junctions, which are clusters of intercellular channels that provide conduits for the diffusion of signaling molecules and a pathway of low resistance for the spread of electrical currents, a form of signaling characteristic of brain cells. Given the radical differences in the strategy of communication and the involved molecules, it is generally perceived that these two forms of communication operate independently. However, there is a growing body of evidence indicating that these two forms of transmission rather extensively interact, both during brain development and in adulthood (for review see [2]), and a new study by Miller et al. [3] reported in this issue of Current Biology now shows that the formation of electrical and chemical synapses during development requires common regulatory steps. Synaptic transmission is a complex cellular function that requires the interaction of multiple proteins. Neurobeachin is a multidomain scaffolding protein identified during screens for novel synaptic proteins that was found to be essential for synaptic transmission [4,5]. This protein is believed to be involved in neuronal post-Golgi membrane trafficking and it was found associated with pleomorphic tubulovesicular endomembranes at the trans side of the Golgi apparatus and at the postsynaptic membrane in some synapses [4]. Analysis of mice lacking Neurobeachin indicated a clear synaptic function for this protein. Consistent with its requirement for neuromuscular transmission [6], Neurobeachin null-mutant mice are paralyzed and die at perinatal ages
Electrical synapse
Chemical synapse
Presynaptic neuron Ca++
Postsynaptic neuron
Neurobeachin
Current Biology
Figure 1. Neurobeachin regulates the formation of chemical and electrical synapses. The cartoon summarizes major differences between the mechanisms of chemical (left) and electrical (right) synaptic transmission. Yellow dashed areas represent protein scaffolds associated with neurotransmitter receptors (left) and gap junction channels (right). Neurobeachin is required only at the postsynaptic neuron for the formation of both chemical and electrical synapses.
[5,7]. These animals also exhibited reduced synaptic responses at central synapses and a reduction in the surface expression of glutamate (excitatory) and GABA (inhibitory) receptors, which seem to accumulate in the biosynthetic pathway [8]. While the direct association of Neurobeachin to scaffolding proteins involved in trafficking of glutamate receptors during synaptogenesis has been established [8], the reduction in surface expression of GABA receptors (whose trafficking involves a different set of scaffolding proteins) suggests that this complex multidomain protein is capable of acting as a scaffold for binding a wide range of proteins. Thus, both excitatory and inhibitory chemical synapses require
Neurobeachin for their formation and proper function. The paper by Miller et al. provides conclusive evidence indicating that Neurobeachin is also required for the formation of gap junction-mediated electrical synapses. Combining the power of zebrafish forward genetics and the analytical advantages of identifiable synapses participating in a well-established neuronal network such as the Mauther cell escape system [9], the paper elegantly demonstrates that mutant zebrafish lacking Neurobeachin show a deficit in the formation of glycinergic synapses and, surprisingly, of electrical synapses. Gap junction channels have been shown to actively traffic at rates that are comparable to those of
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glutamate receptors [10,11] including at Mauthner cell electrical synapses where it was proposed it might underlie regulation of the synaptic strength [11]. In analogy to chemical synapses, Neurobeachin could influence electrical transmission by regulating the traffic of gap junction channels via interactions with scaffolding proteins that are specific for this modality of communication. From a more general point of view, the results indicate that all forms of synaptic communication, regardless of sign (excitatory or inhibitory), molecular composition or ultimate mechanism of transmission, share common developmental steps, revealing an unexpected unity of interneuronal communication. Such unity is further emphasized by recent findings in the Drosophila escape network where the formation of electrical and chemical synapses was found to be co-regulated by the transcription factor Engrailed [12], suggesting that invertebrates and vertebrates share common strategies of interneuronal communication. The second surprising finding was that Neurobeachin is only required postsynaptically for the formation of both chemical and electrical synapses. Chimera analysis in zebrafish demonstrated that Neurobeachin was necessary only when expressed postsynaptically. In contrast to chemical synapses that have a distinct asymmetry in the molecular composition of pre- and postsynaptic sites (specialized in transmitter and receptor clustering, respectively), gap junctions are perceived as symmetric structures, as a single intercellular gap junction channel is formed by the apposition of two hemichannels contributed by each of the coupled cells (Figure 1). Recent data indicate that vertebrate electrical synapses (as some in invertebrates) can be molecularly asymmetric when the contributing hemichannels are formed by different gap junction channel-forming proteins [13]. The results by Miller et al. suggest that Neurobeachin has an important postsynaptic function at electrical synapses. Gap junctions are currently considered part of large macromolecular complexes that contain, in addition to the channel-forming proteins or ‘connexins’, a number of associated proteins that support their function [14]. The detailed composition of this
scaffold at electrical synapses is currently unknown and it could potentially be as complex as that of postsynaptic densities at glutamatergic synapses [15]. Given its established role as a scaffolding protein in membrane trafficking, Neurobeachin could participate or closely interact with proteins that form this complex. Because Neurobeachin was found to be required only postsynaptically, the results of Millet et al. suggest that differences in the molecular composition of electrical synapses might not be restricted to the intercellular channel itself [13] but could also include asymmetries in the molecular composition of the scaffold that regulates the function of these channels. Interestingly, Neurobeachin has recently been identified as a candidate gene for autism [16] and heterozygous mice lacking one copy of the Neurobeachin gene were reported to have behavioral deficits that are reminiscent of symptoms observed in autistic patients [17]. Considered by some as a disorder of early synaptic development [18] the results reported by Miller et al. suggest that electrical synapses could contribute, together with alterations in chemical transmission [17], to the pathological processes underlying autism spectrum disorders. Consistent with this possibility, it was suggested that brain desynchronization could contribute to autism [19]. Disruption of electrical synapses formed by the gap junction-forming protein connexin 36 in the inferior olive (a brainstem structure involved in fine motor control that heavily relies in electrical synapses) might impede the synchronization required for the development of various motor acts, including the acquisition of normal language skills [19]. Electrical synapses are known to promote coordinated neuronal activity and are primarily formed by connexin 36, which is widely expressed in mammalian brain [20]. Electrical and chemical synapses closely interact during brain development and early disruption of electrical synapse formation can lead to defects in the formation of chemical synapses (for review see [2]). In this way, a reduction in the formation of electrical synapses would lead not only to decreased synchronization of neuronal activity but also to deficits in the formation of chemical synapses, resulting in defects and subsequent
dysfunction of critical neural networks. Because electrical synapses in the Mauthner cell network are formed by fish homologs of connexin 36 [13], the data reported in Miller et al. have important pathological implications and opens a new avenue of investigation of the mechanisms underlying autism spectrum disorders. Thus, altogether the results suggest that, rather than electrical or chemical, synaptic communication should be considered a single entity, which is electrical and chemical, and that information within neural networks is simultaneously communicated by combining these two complementary modalities of synaptic transmission. References 1. Tansey, E.M. (1997). Not committing barbarisms: Sherrington and the synapse, 1897. Brain Res. Bull. 44, 211–212. 2. Pereda, A.E. (2014). Electrical synapses and their functional interactions with chemical synapses. Nat. Rev. Neurosci. 15, 250–263. 3. Miller, A.C., Voelker, L.H., Shah, A.N., and Moens, C.B. (2015). Neurobeachin is required postsynaptically for electrical and chemical synapse formation. Curr. Biol. 25, 16–28. 4. Wang, X., Herberg, F.W., Laue, M.M., Wullner, C., Hu, B., Petrasch-Parwez, E., and Kilimann, M.W. (2000). Neurobeachin: A protein kinase A-anchoring, beige/ Chediak-higashi protein homolog implicated in neuronal membrane traffic. J. Neurosci. 20, 8551–8565. 5. Nair, R., Lauks, J., Jung, S., Cooke, N.E., de Wit, H., Brose, N., Kilimann, M.W., Verhage, M., and Rhee, J. (2013). Neurobeachin regulates neurotransmitter receptor trafficking to synapses. J. Cell Biol. 200, 61–80. 6. Su, Y., Balice-Gordon, R.J., Hess, D.M., Landsman, D.S., Minarcik, J., Golden, J., Hurwitz, I., Liebhaber, S.A., and Cooke, N.E. (2004). Neurobeachin is essential for neuromuscular synaptic transmission. J. Neurosci. 24, 3627–3636. 7. Medrihan, L., Rohlmann, A., Fairless, R., Andrae, J., Do¨ring, M., Missler, M., Zhang, W., and Kilimann, M.W. (2009). Neurobeachin, a protein implicated in membrane protein traffic and autism, is required for the formation and functioning of central synapses. J. Physiol. 587, 5095–5106. 8. Lauks, J., Klemmer, P., Farzana, F., Karupothula, R., Zalm, R., Cooke, N.E., Li, K.W., Smit, A.B., Toonen, R., and Verhage, M. (2012). Synapse associated protein 102 (SAP102) binds the C-terminal part of the scaffolding protein neurobeachin. PLoS One 7, e39420. 9. Korn, H., and Faber, D.S. (2005). The Mauthner cell half a century later: a neurobiological model for decision-making? Neuron 47, 13–28. 10. Laird, D.W. (1996). The life cycle of a connexin: gap junction formation, removal, and degradation. J. Bioenerg. Biomembr. 28, 311–318. 11. Flores, C.E., Nannapaneni, S., Davidson, K.G.V., Yasumura, T., Bennett, M.V.L., Rash, J.E., and Pereda, A.E. (2012). Trafficking of gap junction channels at a vertebrate electrical synapse in vivo. Proc. Natl. Acad. Sci. USA 109, E573–E582. 12. Pe´zier, A., Jezzini, S.H., Marie, B., and Blagburn, J.M. (2014). Engrailed alters the specificity of synaptic connections of Drosophila auditory neurons with the giant fiber. J. Neurosci. 34, 11691–11704. 13. Rash, J.E., Curti, S., Vanderpool, K.G., Kamasawa, N., Nannapaneni, S., PalaciosPrado, N., Flores, C.E., Yasumura, T., O’Brien, J., Lynn, B.D., et al. (2013). Molecular
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and functional asymmetry at a vertebrate electrical synapse. Neuron 79, 957–969. 14. Herve´, J.-C., Bourmeyster, N., and Sarrouilhe, D. (2004). Diversity in protein-protein interactions of connexins: emerging roles. Biochim. Biophys. Acta 1662, 22–41. 15. Lynn, B.D., Li, X., and Nagy, J.I. (2012). Under construction: building the macromolecular superstructure and signaling components of an electrical synapse. J. Membr. Biol. 245, 303–317. 16. Volders, K., Nuytens, K., and Creemers, J.W.M. (2011). The autism candidate gene Neurobeachin encodes a scaffolding protein
implicated in membrane trafficking and signaling. Curr. Mol. Med. 11, 204–217. 17. Nuytens, K., Gantois, I., Stijnen, P., Iscru, E., Laeremans, A., Serneels, L., Van Eylen, L., Liebhaber, S.A., Devriendt, K., Balschun, D., et al. (2013). Haploinsufficiency of the autism candidate gene Neurobeachin induces autism-like behaviors and affects cellular and molecular processes of synaptic plasticity in mice. Neurobiol. Dis. 51, 144–151. 18. Zoghbi, H.Y. (2003). Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302, 826–830. 19. Welsh, J.P., Ahn, E.S., and Placantonakis, D.G. (2005). Is autism due to brain
Linguistics: Evolution and Language Change Linguists have long identified sound changes that occur in parallel. Now novel research shows how Bayesian modeling can capture complex concerted changes, revealing how evolution of sounds proceeds. Claire Bowern English speakers who study languages such as German, French, or Spanish are accustomed to coming across words that are similar to their English counterparts. For example, many words that start with p in English start with pf in German, such as plum – Pflaume, pan – Pfanne, penny – Pfennig, and so on. Sister languages show many such regularities, and this has formed the cornerstone for research on language change for nearly two centuries [1,2]. These regularities have allowed linguists to discover many of the processes of language evolution, and how language evolution may be similar to biological evolution. Now, in this issue of Current Biology, Hruschka and colleagues [3] have identified regular sound change as a process similar to concerted evolution in biology. They provide the first statistical model which allows us to study the properties of regular sound change systematically, as well as to compare it to concerted evolution. How Sound Change Works All languages have a set of distinctive sounds, called ‘phonemes’. These are abstract sound categories, which in combination make up words. The word pat, for example, has three phonemes (p, a, and t). The substitution of one phoneme for another changes the meaning of the word, or turns a word
into a non-word. For example, the difference between pat and cat is the first phoneme (p in the first case, k in the second). Phonemes are articulated in different ways. The realization phonemes change according to the position at which they occur in the word, the surrounding phonemes, and physiological traits of the speaker pronouncing the word. For example, the pronunciation of the /k/ phoneme in cat is different from the same phoneme in key. In the latter word, the front vowel pulls the tongue blade forward, leading to a more forward pronunciation. Aspiration is another example. Consider the difference between the t in pat and the t in tap. In the second case, the t has a puff of air (called ‘aspiration’) which is absent from the t in pat. However, no English speaker would consider that pat and tap don’t otherwise have the same phonemes. Finally, the distinctive realization of phonemes is what produces different accents. The distinction between phonemes and their realization is somewhat akin to the genotype–phenotype distinction in biology. The pronunciation of phonemes can change over time. This is called ‘sound change’. Within a language, individuals have different realizations of phonemes. These realizations are subject to selection pressures at both the individual and population level [4]. For example, some variants undergo positive selection and spread
desynchronization? Int. J. Dev. Neurosci. 23, 253–263. 20. Condorelli, D.F., Belluardo, N., TrovatoSalinaro, A., and Mudo`, G. (2000). Expression of Cx36 in mammalian neurons. Brain Res. Brain Res. Rev. 32, 72–85.
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA. E-mail: [email protected] http://dx.doi.org/10.1016/j.cub.2014.11.029
because they are easier to perceive. In our example of the different realizations of k above, for example, a fronted k before a front vowel enhances the cues for the following vowel. Other variants may be positively or negatively selected because they are associated with particular social groups [5]. Over time, these changes may lead to changes in the phonemes themselves. In my German example above, for example, p has become an affricate pf. Linguistics and Biology At this point, biologists will no doubt be thinking of numerous parallels between linguistic and biological evolution. Words are somewhat like genes: they are transmitted vertically, and the nucleotide or phoneme sequences they comprise can change individually or concertedly. There are many broad similarities between linguistic and biological evolution [4,6]; for example, both involve homologous units which descend from common ancestors, which allow us to trace the history of those descent patterns using evolutionary models. ‘Concerted change’ is central to historical linguistics. It was the regularities in correspondences which first allowed linguists to provide principled definitions of language relationships [7], by showing that such changes lead to systematic similarities which could not arise by chance. Sporadic, irregular changes do occur, but they are concentrated in certain sound sequences, or are the result of changes in word structure, or reflect loans from related languages. Though the parallels between linguistic and biological evolution have been discussed since Darwin [8,9], until the last ten years the two disciplines have used different