Neuropharmacology xxx (2013) 1e2
Contents lists available at ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Editorial
The complexity of homeostasis at the synapse Homeostasis is a general feature of most biological systems, this concept has only recently been applied to the functioning of the nervous system. Here homeostasis functions to stabilize the activity of a neuron or neuronal circuit in the face of perturbations. Early evidence for homeostasis was seen in the stability of central pattern generators, such as the somatogastric ganglion, which are able to maintain rhythmicity in the face of a wide range of alterations. However, this stability was generally achieved through changes in intrinsic currents and not synaptic connections. Modeling studies have long recognized that negative feedback at synapses would be necessary to maintain stability in plastic circuits, and some early learning rules, such as BCM theory, incorporated aspects of negative feedback to account for experimental results. Homeostatic synaptic plasticity (HSP) was first experimentally demonstrated in 1998 by the Turrigiano and Huganir groups (O’Brien et al., 1998; Turrigiano et al., 1998), using chronic activity manipulations of dissociated neuronal cultures to demonstrate that synaptic strength, like other aspects of neuronal function, is homeostatically regulated. HSP has since been documented in a number of in vitro and in vivo systems, many of which will be discussed in this special issue. Several components of synapse appear to be under homeostatic regulation, including the pre-synapse, the post-synapse, and the surrounding glia. While there is a growing literature on homeostatic synaptic plasticity, it is still a relatively new field and many fundamental issues remain to be determined. HSP appears to be a broad category of plasticity, with potentially many subtypes that may act in parallel in the same system or be restricted to one cell type or induction paradigm. Chen et al. (2013) and Pribiag and Stellwagen (2013) discuss mechanisms underlying distinct subtypes of HSP, while Thalhammer and Cingolani (2013) review the contribution of cell adhesion molecules to the process. Lee et al. (2013) will explicitly discuss the diversity of types of HSP, with a focus on synapse specific versus global forms of homeostatic plasticity. These reviews all address the mechanisms of the strengthening (scaling up) of excitatory synapses during chronic reductions of activity. Siddoway et al. (2013) will compliment this with a discussion of the mechanisms of the weakening (scaling down) of excitatory synapses following heightened periods of neuronal activity. Important advances have been made in the translation of homeostatic plasticity observed in reduced preparations (particularly in dissociated culture systems) to the functioning of the intact nervous system. In particular, HSP appears to be active during early stages of development. Whitt et al. (2013) will review the work on HSP in the developing neocortex and Wenner (2013) will discuss HSP in the developing spinal cord, while Frank (2013) will focus on the drosophila larval neuromuscular junction. And Borodinsky et al. (2013) will broaden the scope beyond focusing exclusively on
changes in synaptic strength by examining homeostatic changes in neurotransmitter phenotype during development. Together, these papers will review the current state in the field of HSP, and address many of the on-going controversies. One additional issue would be the appropriateness of the name “homeostatic synaptic plasticity” itself. While clearly a form of synaptic plasticity, the term “homeostatic” doesn’t necessarily encompass all aspects of this type of plasticity and it is possible that “allostatic” might be more appropriate. “Homeostasis” in physiological systems is generally defined as the mechanisms that maintain stability within the systems and hold parameters within specific limits. This implies that deviation from a normal set point is automatically corrected by negative feedback, such as for body osmolality and blood pressure. In contrast, the principle of “allostasis” proposes maintenance of stability without a static set point; rather, the parameters of a physiological system are matched to the chronic demand (Sterling, 2012). During allostasis, there is a continuous re-evaluation of the system’s needs and readjustments to a new set point depending on the situation. Although allostasis is far more complex then homeostasis and is often used to describe interaction between central and the peripheral systems (for example, the stress response), we suggest that “homeostatic synaptic scaling” is a complex process that likely involves a broad range of ‘normal’ activity levels without a single distinct set point; therefore allostatic plasticity may be more suitable to describe the effect of perturbation in neuronal networks. Further, there appears to be considerable tolerance of temporary shifts in activity levels, as HSP is a relatively slow process requiring perturbations lasting for hours or days. Most classic homeostatic systems react quickly to maintain systems within narrow physiological ranges. The concept of allostasis also includes the idea of “allostatic load”, which is the cost the body pays to adapt to chronic deviation from the normal state (McEwen, 2000). In the case of HSP, if the perturbation of the system is prolonged, the chronic activation of the mechanisms involved could eventually lead to neuronal dysfunction. For example, the cytokine TNFa was shown to be required for HSP following the chronic blocked of activity. However, high and sustained levels of TNFa can lead to neurodegeneration in part through activation of programmed cells death pathways. Therefore, incorporating some of the unique characteristics of allostasis may have more explanatory power than homeostasis in characterizing the synaptic scaling responses required in an ever changing neuronal network.
References Borodinsky, L.N., Belgacem, Y.H., Swapna, I., Sequerra, E.B., 2013. Dynamic regulation of neurotransmitter specification: relevance to nervous system homeostasis. Neuropharmacology 75.
0028-3908/$ e see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.neuropharm.2013.10.019
Please cite this article in press as: Stellwagen, D., Lewitus, G.M., The complexity of homeostasis at the synapse, Neuropharmacology (2013), http://dx.doi.org/10.1016/j.neuropharm.2013.10.019
2
Editorial / Neuropharmacology xxx (2013) 1e2
Chen, L., Lau, A.G., Sarti, F., 2013. Synaptic retinoic acid signaling and homeostatic synaptic plasticity. Neuropharmacology 75. Frank, C.A., 2013. Homeostatic plasticity at the Drosophila neuromuscular junction. Neuropharmacology 75. Lee, K.F.H., Soares, C., Béïque, J.-C., 2013. Tuning into diversity of homeostatic synaptic plasticity. Neuropharmacology 75. McEwen, B.S., 2000. Allostasis, allostatic load, and the aging nervous system: role of excitatory amino acids and excitotoxicity. Neurochem. Res. 25, 1219e1231. O’Brien, R.J., Kamboj, S., Ehlers, M.D., Rosen, K.R., Fischbach, G.D., Huganir, R.L., 1998. Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron 21, 1067e1078. Pribiag, H., Stellwagen, D., 2013. Neuroimmune regulation of homeostatic synaptic plasticity. Neuropharmacology 75. Siddoway, B., Hou, H., Xia, H., 2013. Molecular mechanisms of homeostatic synaptic downscaling. Neuropharmacology 75. Sterling, P., 2012. Allostasis: a model of predictive regulation. Physiol. Behav. 106, 5e15. Thalhammer, A., Cingolani, L.A., 2013. Cell adhesion and homeostatic synaptic plasticity. Neuropharmacology 75.
Turrigiano, G.G., Leslie, K.R., Desai, N.S., Rutherford, L.C., Nelson, S.B., 1998. Activitydependent scaling of quantal amplitude in neocortical neurons. Nature 391, 892e896. Wenner, P., 2013. Homeostatic synaptic plasticity in developing spinal networks driven by excitatory GABAergic currents. Neuropharmacology 75. Whitt, Jessica L., Petrus, Emily, Lee, Hey-Kyoung, 2013. Experience-dependent homeostatic synaptic plasticity in neocortex. Neuropharmacology 75.
D. Stellwagen*, G.M. Lewitus Centre for Research in Neuroscience, Research Institute of the McGill University Health Center, Montreal General Hospital, L7-132, 1650 Cedar Av, Montreal, Quebec H3G 1A4, Canada * Corresponding author. Tel.: þ1 514 934 1934. E-mail address: [email protected] (D. Stellwagen).
Please cite this article in press as: Stellwagen, D., Lewitus, G.M., The complexity of homeostasis at the synapse, Neuropharmacology (2013), http://dx.doi.org/10.1016/j.neuropharm.2013.10.019
Contents lists available at ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Editorial
The complexity of homeostasis at the synapse Homeostasis is a general feature of most biological systems, this concept has only recently been applied to the functioning of the nervous system. Here homeostasis functions to stabilize the activity of a neuron or neuronal circuit in the face of perturbations. Early evidence for homeostasis was seen in the stability of central pattern generators, such as the somatogastric ganglion, which are able to maintain rhythmicity in the face of a wide range of alterations. However, this stability was generally achieved through changes in intrinsic currents and not synaptic connections. Modeling studies have long recognized that negative feedback at synapses would be necessary to maintain stability in plastic circuits, and some early learning rules, such as BCM theory, incorporated aspects of negative feedback to account for experimental results. Homeostatic synaptic plasticity (HSP) was first experimentally demonstrated in 1998 by the Turrigiano and Huganir groups (O’Brien et al., 1998; Turrigiano et al., 1998), using chronic activity manipulations of dissociated neuronal cultures to demonstrate that synaptic strength, like other aspects of neuronal function, is homeostatically regulated. HSP has since been documented in a number of in vitro and in vivo systems, many of which will be discussed in this special issue. Several components of synapse appear to be under homeostatic regulation, including the pre-synapse, the post-synapse, and the surrounding glia. While there is a growing literature on homeostatic synaptic plasticity, it is still a relatively new field and many fundamental issues remain to be determined. HSP appears to be a broad category of plasticity, with potentially many subtypes that may act in parallel in the same system or be restricted to one cell type or induction paradigm. Chen et al. (2013) and Pribiag and Stellwagen (2013) discuss mechanisms underlying distinct subtypes of HSP, while Thalhammer and Cingolani (2013) review the contribution of cell adhesion molecules to the process. Lee et al. (2013) will explicitly discuss the diversity of types of HSP, with a focus on synapse specific versus global forms of homeostatic plasticity. These reviews all address the mechanisms of the strengthening (scaling up) of excitatory synapses during chronic reductions of activity. Siddoway et al. (2013) will compliment this with a discussion of the mechanisms of the weakening (scaling down) of excitatory synapses following heightened periods of neuronal activity. Important advances have been made in the translation of homeostatic plasticity observed in reduced preparations (particularly in dissociated culture systems) to the functioning of the intact nervous system. In particular, HSP appears to be active during early stages of development. Whitt et al. (2013) will review the work on HSP in the developing neocortex and Wenner (2013) will discuss HSP in the developing spinal cord, while Frank (2013) will focus on the drosophila larval neuromuscular junction. And Borodinsky et al. (2013) will broaden the scope beyond focusing exclusively on
changes in synaptic strength by examining homeostatic changes in neurotransmitter phenotype during development. Together, these papers will review the current state in the field of HSP, and address many of the on-going controversies. One additional issue would be the appropriateness of the name “homeostatic synaptic plasticity” itself. While clearly a form of synaptic plasticity, the term “homeostatic” doesn’t necessarily encompass all aspects of this type of plasticity and it is possible that “allostatic” might be more appropriate. “Homeostasis” in physiological systems is generally defined as the mechanisms that maintain stability within the systems and hold parameters within specific limits. This implies that deviation from a normal set point is automatically corrected by negative feedback, such as for body osmolality and blood pressure. In contrast, the principle of “allostasis” proposes maintenance of stability without a static set point; rather, the parameters of a physiological system are matched to the chronic demand (Sterling, 2012). During allostasis, there is a continuous re-evaluation of the system’s needs and readjustments to a new set point depending on the situation. Although allostasis is far more complex then homeostasis and is often used to describe interaction between central and the peripheral systems (for example, the stress response), we suggest that “homeostatic synaptic scaling” is a complex process that likely involves a broad range of ‘normal’ activity levels without a single distinct set point; therefore allostatic plasticity may be more suitable to describe the effect of perturbation in neuronal networks. Further, there appears to be considerable tolerance of temporary shifts in activity levels, as HSP is a relatively slow process requiring perturbations lasting for hours or days. Most classic homeostatic systems react quickly to maintain systems within narrow physiological ranges. The concept of allostasis also includes the idea of “allostatic load”, which is the cost the body pays to adapt to chronic deviation from the normal state (McEwen, 2000). In the case of HSP, if the perturbation of the system is prolonged, the chronic activation of the mechanisms involved could eventually lead to neuronal dysfunction. For example, the cytokine TNFa was shown to be required for HSP following the chronic blocked of activity. However, high and sustained levels of TNFa can lead to neurodegeneration in part through activation of programmed cells death pathways. Therefore, incorporating some of the unique characteristics of allostasis may have more explanatory power than homeostasis in characterizing the synaptic scaling responses required in an ever changing neuronal network.
References Borodinsky, L.N., Belgacem, Y.H., Swapna, I., Sequerra, E.B., 2013. Dynamic regulation of neurotransmitter specification: relevance to nervous system homeostasis. Neuropharmacology 75.
0028-3908/$ e see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.neuropharm.2013.10.019
Please cite this article in press as: Stellwagen, D., Lewitus, G.M., The complexity of homeostasis at the synapse, Neuropharmacology (2013), http://dx.doi.org/10.1016/j.neuropharm.2013.10.019
2
Editorial / Neuropharmacology xxx (2013) 1e2
Chen, L., Lau, A.G., Sarti, F., 2013. Synaptic retinoic acid signaling and homeostatic synaptic plasticity. Neuropharmacology 75. Frank, C.A., 2013. Homeostatic plasticity at the Drosophila neuromuscular junction. Neuropharmacology 75. Lee, K.F.H., Soares, C., Béïque, J.-C., 2013. Tuning into diversity of homeostatic synaptic plasticity. Neuropharmacology 75. McEwen, B.S., 2000. Allostasis, allostatic load, and the aging nervous system: role of excitatory amino acids and excitotoxicity. Neurochem. Res. 25, 1219e1231. O’Brien, R.J., Kamboj, S., Ehlers, M.D., Rosen, K.R., Fischbach, G.D., Huganir, R.L., 1998. Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron 21, 1067e1078. Pribiag, H., Stellwagen, D., 2013. Neuroimmune regulation of homeostatic synaptic plasticity. Neuropharmacology 75. Siddoway, B., Hou, H., Xia, H., 2013. Molecular mechanisms of homeostatic synaptic downscaling. Neuropharmacology 75. Sterling, P., 2012. Allostasis: a model of predictive regulation. Physiol. Behav. 106, 5e15. Thalhammer, A., Cingolani, L.A., 2013. Cell adhesion and homeostatic synaptic plasticity. Neuropharmacology 75.
Turrigiano, G.G., Leslie, K.R., Desai, N.S., Rutherford, L.C., Nelson, S.B., 1998. Activitydependent scaling of quantal amplitude in neocortical neurons. Nature 391, 892e896. Wenner, P., 2013. Homeostatic synaptic plasticity in developing spinal networks driven by excitatory GABAergic currents. Neuropharmacology 75. Whitt, Jessica L., Petrus, Emily, Lee, Hey-Kyoung, 2013. Experience-dependent homeostatic synaptic plasticity in neocortex. Neuropharmacology 75.
D. Stellwagen*, G.M. Lewitus Centre for Research in Neuroscience, Research Institute of the McGill University Health Center, Montreal General Hospital, L7-132, 1650 Cedar Av, Montreal, Quebec H3G 1A4, Canada * Corresponding author. Tel.: þ1 514 934 1934. E-mail address: [email protected] (D. Stellwagen).
Please cite this article in press as: Stellwagen, D., Lewitus, G.M., The complexity of homeostasis at the synapse, Neuropharmacology (2013), http://dx.doi.org/10.1016/j.neuropharm.2013.10.019
