Synaptic Tenacity or Lack Thereof: Spontaneous Remodeling of Synapses
Authors: Noam E. Ziv, Naama Brenner
Journal: Trends in Neurosciences (2017)

Synaptic remodeling is driven by both activity-dependent and spontaneous processes. The magnitude of spontaneous synaptic remodeling is comparable with that of activity-dependent remodeling. Spontaneous synaptic remodeling processes can give rise to a full repertoire of synaptic sizes even in the complete absence of activity. While spontaneous remodeling processes drive continuous fluctuations in the properties of individual synapses, stable and skewed distributions of the same properties emerge as population invariants. Scaling of synaptic size distributions appears as a population-level phenomenon when spontaneous remodeling processes are modulated by perturbations of spontaneous network activity. Synaptic plasticity – the directed modulation of synaptic connections by specific activity histories or physiological signals – is believed to be a major mechanism for the modification of neuronal network function. This belief, however, has a 'flip side': the supposition that synapses do not change spontaneously in manners unrelated to such signals. Contrary to this supposition, recent studies reveal that synapses do change spontaneously, and to a fairly large extent. Here we review experimental results on spontaneous synaptic remodeling, its relative contributions to total synaptic remodeling, its statistical characteristics, and its physiological importance. We also address challenges it poses and avenues it opens for future experimental and theoretical research. Synaptic plasticity – the directed modulation of synaptic connections by specific activity histories or physiological signals – is believed to be a major mechanism for the modification of neuronal network function. This belief, however, has a 'flip side': the supposition that synapses do not change spontaneously in manners unrelated to such signals. Contrary to this supposition, recent studies reveal that synapses do change spontaneously, and to a fairly large extent. Here we review experimental results on spontaneous synaptic remodeling, its relative contributions to total synaptic remodeling, its statistical characteristics, and its physiological importance. We also address challenges it poses and avenues it opens for future experimental and theoretical research. At a conceptual level, the central nervous system (CNS) comprises a vast network of excitable cells connected by specialized junctions known as synapses. Long before excitability and synaptic transmission were fully understood, scholars such as William James [1James, W. (1890) Association. In The Principles of Psychology (Vol. 2), pp. 550–604, Henry HoltGoogle Scholar] suggested that changes to connections ('tracts of conduction'), driven by sequential or concomitant activation of 'elementary brain-processes', might explain the formation of new associations and the learning of new tasks. In fact, James credits this idea to yet earlier scholars (e.g., Descartes, Locke) and notes that they 'hit upon this explanation, which modern science has not yet succeeded in improving' [1James, W. (1890) Association. In The Principles of Psychology (Vol. 2), pp. 550–604, Henry HoltGoogle Scholar]. Years later, Donald Hebb rephrased this idea, using it as a cornerstone for constructs such as cell assemblies, thereafter used to explain network function and ultimately behavior in physiological terms [2Hebb D.O. Organization of Behavior: A Neuropsychological Theory. John Wiley and Sons, 1949Google Scholar]. Inspired by these theories, and armed with increasingly powerful methodologies, numerous investigators have convincingly demonstrated that activity histories (see Glossary) can influence and change such tracts of conduction, now largely identified as chemical synapses. The resulting changes, generally referred to as synaptic plasticity, are thus commonly viewed as evidence for this venerable theory. The long-held framework described above has an implicit yet often ignored corollary, which is the supposition that synapses, when not driven to change by particular activity patterns or histories, retain their properties indefinitely. This supposition would seem to be essential because without it, spontaneously occurring changes might drive spurious modifications in network function or undo physiologically relevant ones. Thus, to fully appreciate the importance and limitations of synaptic plasticity, it is essential to measure and understand the capacity of synapses to maintain their particular properties (e.g., probability of release, total receptor conductance, size, morphology, ultrastructure, composition) over behaviorally relevant timescales. We refer to this capacity as synaptic tenacity [3Minerbi A. et al.Long-term relationships between synaptic tenacity, synaptic remodeling, and network activity.PLoS Biol. 2009; 7e1000136Crossref PubMed Scopus (120) Google Scholar, 4Fisher-Lavie A. et al.Use dependence of presynaptic tenacity.J. Neurosci. 2011; 31: 16770-16780Crossref PubMed Scopus (26) Google Scholar, 5Zeidan A. Ziv N.E. Neuroligin-1 loss is associated with reduced tenacity of excitatory synapses.PLoS One. 2012; 7e42314Crossref PubMed Scopus (27) Google Scholar, 6Rubinski A. Ziv N.E. Remodeling and tenacity of inhibitory synapses: relationships with network activity and neighboring excitatory synapses.PLoS Comput. Biol. 2015; 11e1004632Crossref PubMed Scopus (20) Google Scholar]. The aim of this Opinion is to discuss challenges to the notion of synaptic tenacity that come from general biological considerations and experimental findings. Such findings collectively suggest that synaptic tenacity is inherently limited, since synapses do change spontaneously and to a fairly large extent. We survey these findings and discuss their implications in light of the supposition mentioned above. We then present principles emerging from recent literature on the manners by which spontaneous processes might govern dynamic and statistical properties of synaptic populations. We end by formulating several key questions concerning relationships between spontaneous remodeling, underlying biological processes, neuronal activity, and network function. CNS synapses are micrometer-size, intricate assemblies of diverse molecules (e.g., receptors, ion channels, synaptic vesicle, scaffolding, cytoskeletal, adhesion, and signaling molecules). Typical lifetimes of synaptic molecules (i.e., days; see [7Cohen L.D. Ziv N.E. Recent insights on principles of synaptic protein degradation.F1000Research. 2017; 6: 675Crossref PubMed Scopus (24) Google Scholar]) are orders of magnitude shorter than the lifetimes of many, if not most CNS synapses (weeks and months, and in some species probably years [8Holtmaat A. Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain.Nat. Rev. Neurosci. 2009; 10: 647-658Crossref PubMed Scopus (1325) Google Scholar, 9Attardo A. et al.Impermanence of dendritic spines in live adult CA1 hippocampus.Nature. 2015; 523: 592-596Crossref PubMed Scopus (227) Google Scholar, 10Qiao Q. et al.Long-term stability of axonal boutons in the mouse barrel cortex.Dev. Neurobiol. 2016; 76: 252-621Crossref PubMed Scopus (30) Google Scholar]; see [11Berry K.P. Nedivi E. Spine dynamics: are they all the same?.Neuron. 2017; 96: 43-55Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar] for a recent review). Consequently, the maintenance of synaptic connections involves continuous removal and degradation of molecules and their substitution with freshly synthesized copies. Given that CNS synapses are often remote from the neuron's somatic biosynthetic machinery (residing at distances of many centimeters or even meters, in some organisms), long-term synaptic maintenance is a remarkable biological feat [12Bezprozvanny I. Hiesinger P.R. The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration.Mol. Neurodegener. 2013; 8: 23Crossref PubMed Scopus (66) Google Scholar, 13Wang Y.C. et al.Presynaptic protein homeostasis and neuronal function.Curr. Opin. Genet. Dev. 2017; 44: 38-46Crossref PubMed Scopus (38) Google Scholar]. Importantly, however, given these logistic challenges and the low copy numbers of many molecules at individual synapses, it is probably unrealistic to expect that synapses maintain their particular contents and, by extension, their functional properties with pinpoint precision (see [14Kosik K.S. Life at low copy number: how dendrites manage with so few mRNAs.Neuron. 2016; 92: 1168-1180Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]). This expectation is further challenged by the fact that synapses are not rigid structures but rather are dynamic assemblies of molecules (and organelles) that continuously migrate into, out of, and between neighboring assemblies through lateral diffusion, active trafficking, endocytosis, and exocytosis [15Choquet D. Triller A. The dynamic synapse.Neuron. 2013; 80: 691-703Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 16Ziv N.E. Fisher-Lavie A. Presynaptic and postsynaptic scaffolds: dynamics fast and slow.Neuroscientist. 2014; 20: 439-452Crossref PubMed Scopus (33) Google Scholar]. These molecular dynamics are often further accelerated by cellular processes associated with synaptic transmission, such as membrane recycling and cytoskeletal dynamics. Conceivably, challenges to synaptic tenacity posed by continuous molecular turnover and the myriad molecular dynamics might be met somehow, resulting in roughly stable synaptic properties. More likely, however, molecular dynamics coupled with imprecise proteostasis will drive spontaneous changes in synaptic properties that have little to do with specific activity histories [17Yasumatsu N. et al.Principles of long-term dynamics of dendritic spines.J. Neurosci. 2008; 28: 13592-13608Crossref PubMed Scopus (216) Google Scholar]. As we show next, experimental evidence seems to favor the latter possibility. During development the brain is strongly influenced by experience and activity, yet it seems that activity is largely dispensable for synapse formation per se. Although this conclusion is well established [18Harms K.G. Craig A.M. Synapse composition and organization following chronic activity blockade in cultured hippocampal neurons.J. Comp. Neurol. 2005; 490: 72-84Crossref PubMed Scopus (53) Google Scholar, 19Harms K.J. et al.Synapse-specific regulation of AMPA receptor subunit composition by activity.J. Neurosci. 2005; 25: 6379-6388Crossref PubMed Scopus (59) Google Scholar] (see [20Ziv N.E. Garner C.C. Principles of glutamatergic synapse formation: seeing the forest for the trees.Curr. Opin. Neurobiol. 2001; 11: 536-543Crossref PubMed Scopus (60) Google Scholar] for a review of earlier work), recent studies have highlighted observations that are particularly pertinent to this Opinion. Studies in primary culture have shown that general properties of excitatory and inhibitory synapses are largely preserved even when networks develop in the complete absence of activity. For example, chronic suppression of neurotransmitter release or network activity in primary cultures of hippocampal neurons does not appear to affect synaptic spatial densities, colocalization of pre- and postsynaptic molecules, or the synaptic contents of important postsynaptic density (PSD) proteins (e.g., PSD-95/Dlg4, CaMKIIα, SynGAP, Gephyrin) and neurotransmitter receptor subunits (Gria2/3, GABAAα2) [18Harms K.G. Craig A.M. Synapse composition and organization following chronic activity blockade in cultured hippocampal neurons.J. Comp. Neurol. 2005; 490: 72-84Crossref PubMed Scopus (53) Google Scholar, 19Harms K.J. et al.Synapse-specific regulation of AMPA receptor subunit composition by activity.J. Neurosci. 2005; 25: 6379-6388Crossref PubMed Scopus (59) Google Scholar]. Recently, these findings were confirmed and extended to additional preparations, including the intact brain. In one study [21Sigler A. et al.Formation and maintenance of functional spines in the absence of presynaptic glutamate release.Neuron. 2017; 94: 304-311Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar] (see also [22Varoqueaux F. et al.Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming.Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 9037-9042Crossref PubMed Scopus (418) Google Scholar]), spine types, spine spatial densities, and synaptic currents were examined in hippocampal organotypic cultures prepared from mice in which presynaptic release was abolished (by eliminating the presynaptic proteins Munc13-1 and Munc13-2). These synaptic features were found to be similar to those observed in preparations from control animals, although postsynaptic currents were slightly reduced and less correlated with spine volume. In a second study [23Sando R. et al.Assembly of excitatory synapses in the absence of glutamatergic neurotransmission.Neuron. 2017; 94: 312-321Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar], the near-complete suppression of presynaptic glutamate release in the mouse forebrain (by tetanus toxin expression) was found to have relatively modest effects on synapses and their properties, at least as judged by morphological measures. Although synapse numbers and spine densities were reduced in some brain regions (but not others), dendritic spines of all types formed at normal proportions. These observations – that synapses of all sizes and types form at normal proportions – have profound implications: when synapses and dendritic spines are initially formed, they generally have small volumes and PSDs (e.g., [24Holtmaat A. et al.Experience-dependent and cell-type-specific spine growth in the neocortex.Nature. 2006; 441: 979-983Crossref PubMed Scopus (494) Google Scholar, 25Knott G.W. et al.Spine growth precedes synapse formation in the adult neocortex in vivo.Nat. Neurosci. 2006; 9: 1117-1124Crossref PubMed Scopus (448) Google Scholar, 26Zito K. et al.Rapid functional maturation of nascent dendritic spines.Neuron. 2009; 61: 247-258Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 27Statman A. et al.Synaptic size dynamics as an effectively stochastic process.PLoS Comput. Biol. 2014; 10e1003846Crossref PubMed Scopus (39) Google Scholar]). Their subsequent conversion into large, mushroom-shaped spines is often thought to be driven by activity-dependent potentiation (reviewed in [28Bourne J. Harris K.M. Do thin spines learn to be mushroom spines that remember?.Curr. Opin. Neurobiol. 2007; 17: 381-386Crossref PubMed Scopus (630) Google Scholar, 29Kasai H. et al.Structural dynamics of dendritic spines in memory and cognition.Trends Neurosci. 2010; 33: 121-129Abstract Full Text Full Text PDF PubMed Scopus (596) Google Scholar]; see also [30Meyer D. et al.Balance and stability of synaptic structures during synaptic plasticity.Neuron. 2014; 82: 430-443Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 31Bosch M. et al.Structural and molecular remodeling of dendritic spine substructures during long-term potentiation.Neuron. 2014; 82: 444-459Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar]). However, as mentioned above, large synapses, including mushroom-shaped spines, develop in normal proportions even when activity is essentially nonexistent [18Harms K.G. Craig A.M. Synapse composition and organization following chronic activity blockade in cultured hippocampal neurons.J. Comp. Neurol. 2005; 490: 72-84Crossref PubMed Scopus (53) Google Scholar, 19Harms K.J. et al.Synapse-specific regulation of AMPA receptor subunit composition by activity.J. Neurosci. 2005; 25: 6379-6388Crossref PubMed Scopus (59) Google Scholar, 21Sigler A. et al.Formation and maintenance of functional spines in the absence of presynaptic glutamate release.Neuron. 2017; 94: 304-311Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 23Sando R. et al.Assembly of excitatory synapses in the absence of glutamatergic neurotransmission.Neuron. 2017; 94: 312-321Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. It thus seems that activity-independent processes can generate the full repertoire of synaptic sizes [17Yasumatsu N. et al.Principles of long-term dynamics of dendritic spines.J. Neurosci. 2008; 28: 13592-13608Crossref PubMed Scopus (216) Google Scholar], highlighting the potency of spontaneous synaptic remodeling. Longitudinal observations of individual CNS synapses over many days in mature networks, both in vitro and in vivo, indicate that most synapses are persistent over these timescales, (e.g., [10Qiao Q. et al.Long-term stability of axonal boutons in the mouse barrel cortex.Dev. Neurobiol. 2016; 76: 252-621Crossref PubMed Scopus (30) Google Scholar, 32Carrillo J. et al.The long-term structural plasticity of cerebellar parallel fiber axons and its modulation by motor learning.J. Neurosci. 2013; 33: 8301-8307Crossref PubMed Scopus (16) Google Scholar] but see [9Attardo A. et al.Impermanence of dendritic spines in live adult CA1 hippocampus.Nature. 2015; 523: 592-596Crossref PubMed Scopus (227) Google Scholar]; reviewed in [8Holtmaat A. Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain.Nat. Rev. Neurosci. 2009; 10: 647-658Crossref PubMed Scopus (1325) Google Scholar]), although significant synapse formation and elimination are also observed (reviewed in [33Clopath C. et al.Variance and invariance of neuronal long-term representations.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2017; 37220160161Crossref PubMed Scopus (59) Google Scholar, 34Mongillo G. et al.Intrinsic volatility of synaptic connections – a challenge to the synaptic trace theory of memory.Curr. Opin. Neurobiol. 2017; 46: 7-13Crossref PubMed Scopus (56) Google Scholar, 35Chambers A.R. Rumpel S. 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Neurosci. 2008; 28: 13592-13608Crossref PubMed Scopus (216) Google Scholar, 24Holtmaat A. et al.Experience-dependent and cell-type-specific spine growth in the neocortex.Nature. 2006; 441: 979-983Crossref PubMed Scopus (494) Google Scholar, 36Zuo Y. et al.Development of long-term dendritic spine stability in diverse regions of cerebral cortex.Neuron. 2005; 46: 181-189Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar, 37De Roo M. et al.LTP promotes a selective long-term stabilization and clustering of dendritic spines.PLoS Biol. 2008; 6: e219Crossref PubMed Scopus (167) Google Scholar, 38Loewenstein Y. et al.Multiplicative dynamics underlie the emergence of the log-normal distribution of spine sizes in the neocortex in vivo.J. Neurosci. 2011; 31: 9481-9488Crossref PubMed Scopus (142) Google Scholar]), presynaptic bouton volume [39Grillo F.W. et al.Increased axonal bouton dynamics in the aging mouse cortex.Proc. Natl. Acad. Sci. U. S. 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Neurosci. 2011; 31: 16770-16780Crossref PubMed Scopus (26) Google Scholar, 42Matz J. et al.Rapid structural alterations of the active zone lead to sustained changes in neurotransmitter release.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 8836-8841Crossref PubMed Scopus (114) Google Scholar, 43Fisher-Lavie A. Ziv N.E. Matching dynamics of presynaptic and postsynaptic scaffolds.J. Neurosci. 2013; 33: 13094-13100Crossref PubMed Scopus (16) Google Scholar], and PSD protein content (PSD-95, Gria2, Gephyrin, GKAP, Shank, Zip45/Homer1c) [3Minerbi A. et al.Long-term relationships between synaptic tenacity, synaptic remodeling, and network activity.PLoS Biol. 2009; 7e1000136Crossref PubMed Scopus (120) Google Scholar, 5Zeidan A. Ziv N.E. Neuroligin-1 loss is associated with reduced tenacity of excitatory synapses.PLoS One. 2012; 7e42314Crossref PubMed Scopus (27) Google Scholar, 6Rubinski A. Ziv N.E. Remodeling and tenacity of inhibitory synapses: relationships with network activity and neighboring excitatory synapses.PLoS Comput. Biol. 2015; 11e1004632Crossref PubMed Scopus (20) Google Scholar, 27Statman A. et al.Synaptic size dynamics as an effectively stochastic process.PLoS Comput. Biol. 2014; 10e1003846Crossref PubMed Scopus (39) Google Scholar, 43Fisher-Lavie A. Ziv N.E. Matching dynamics of presynaptic and postsynaptic scaffolds.J. Neurosci. 2013; 33: 13094-13100Crossref PubMed Scopus (16) Google Scholar, 44Marrs G.S. et al.Rapid formation and remodeling of postsynaptic densities in developing dendrites.Nat. Neurosci. 2001; 4: 1006-1013Crossref PubMed Scopus (258) Google Scholar, 45Kuriu T. et al.Differential control of postsynaptic density scaffolds via actin-dependent and -independent mechanisms.J. Neurosci. 2006; 26: 7693-7706Crossref PubMed Scopus (161) Google Scholar, 46Kaufman M. et al.Long-term relationships between cholinergic tone, synchronous bursting and synaptic remodeling.PLoS One. 2012; 7e40980Crossref PubMed Scopus (24) Google Scholar, 47Cane M. et al.The relationship between PSD-95 clustering and spine stability in vivo.J. Neurosci. 2014; 34: 2075-2086Crossref PubMed Scopus (137) Google Scholar, 48Pagès S. et al.Single cell electroporation for longitudinal imaging of synaptic structure and function in the adult mouse neocortex in vivo.Front. Neuroanat. 2015; 9: 36PubMed Google Scholar, 49Gray N.W. et al.Rapid redistribution of synaptic PSD-95 in the neocortex in vivo.PLoS Biol. 2006; 4: e370Crossref PubMed Scopus (268) Google Scholar] fluctuate considerably over these timescales (as illustrated for PSD-95 in Figure 1). Given the strong correlations between these measures and functional synaptic features such as synaptic vesicle release [42Matz J. et al.Rapid structural alterations of the active zone lead to sustained changes in neurotransmitter release.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 8836-8841Crossref PubMed Scopus (114) Google Scholar] and synaptic current amplitudes (reviewed in [8Holtmaat A. Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain.Nat. Rev. Neurosci. 2009; 10: 647-658Crossref PubMed Scopus (1325) Google Scholar, 29Kasai H. et al.Structural dynamics of dendritic spines in memory and cognition.Trends Neurosci. 2010; 33: 121-129Abstract Full Text Full Text PDF PubMed Scopus (596) Google Scholar, 50Nishiyama J. Yasuda R. Biochemical computation for spine structural plasticity.Neuron. 2015; 87: 63-75Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar]), these fluctuations are likely to have functional consequences. Indeed, comparable fluctuations in connection strengths are observed when measured directly [51Tsukamoto-Yasui M. et al.Active hippocampal networks undergo spontaneous synaptic modification.PLoS One. 2007; 2e1250Crossref PubMed Scopus (20) Google Scholar, 52Usami A. et al.Spontaneous plasticity of multineuronal activity patterns in activated hippocampal networks.Neural Plast. 2008; 2008108969Crossref PubMed Scopus (15) Google Scholar, 53Loebel A. et al.Matched pre- and post-synaptic changes underlie synaptic plasticity over long time scales.J. Neurosci. 2013; 33: 6257-6266Crossref PubMed Scopus (28) Google Scholar]. Furthermore, fluctuations tend to occur simultaneously in pre- and postsynaptic scaffolds of the same synapses [43Fisher-Lavie A. Ziv N.E. Matching dynamics of presynaptic and postsynaptic scaffolds.J. Neurosci. 2013; 33: 13094-13100Crossref PubMed Scopus (16) Google Scholar], further supporting their functional significance. As synapses in the aforementioned studies were embedded in active networks, their fluctuations reflect both spontaneous and activity-history-driven processes. Yet even when spontaneous activity is suppressed or eliminated altogether, fluctuations persist [3Minerbi A. et al.Long-term relationships between synaptic tenacity, synaptic remodeling, and network activity.PLoS Biol. 2009; 7e1000136Crossref PubMed Scopus (120) Google Scholar, 6Rubinski A. Ziv N.E. Remodeling and tenacity of inhibitory synapses: relationships with network activity and neighboring excitatory synapses.PLoS Comput. Biol. 2015; 11e1004632Crossref PubMed Scopus (20) Google Scholar, 17Yasumatsu N. et al.Principles of long-term dynamics of dendritic spines.J. Neurosci. 2008; 28: 13592-13608Crossref PubMed Scopus (216) Google Scholar, 40Schuemann A. et al.Structural plasticity of GABAergic axons is regulated by network activity and GABAA receptor activation.Front. Neural Circuits. 2013; 7: 113Crossref PubMed Scopus (27) Google Scholar, 54Dvorkin R. Ziv N.E. Relative contributions of specific activity histories and spontaneous processes to size remodeling of glutamatergic synapses.PLoS Biol. 2016; 14e1002572Crossref PubMed Scopus (27) Google Scholar], although their characteristics can change (see below). These results suggest that in mature networks, as in developing networks, spontaneous synaptic remodeling is significant. The presence of significant activity-independent synaptic remodeling raises an important question: what are the relative contributions of specific activity histories and spontaneous processes to synaptic remodeling? This question might be addressed by comparing the magnitudes of changes they induce. As a rough estimate, changes to PSD sizes following experimental paradigms that induce long-term potentiation (measured using fluorescently tagged variants of PSD-95 and Homer1b) (e.g., [30Meyer D. et al.Balance and stability of synaptic structures during synaptic plasticity.Neuron. 2014; 82: 430-443Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 31Bosch M. et al.Structural and molecular remodeling of dendritic spine substructures during long-term potentiation.Neuron. 2014; 82: 444-459Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar]) seem to be of magnitude similar to that of baseline PSD size fluctuations observed in vivo using similar approaches [47Cane M. et al.The relationship between PSD-95 clustering and spine stability in vivo.J. Neurosci. 2014; 34: 2075-2086Crossref PubMed Scopus (137) Google Scholar, 49Gray N.W. et al.Rapid redistribution of synaptic PSD-95 in the neocortex in vivo.PLoS Biol. 2006; 4: e370Crossref PubMed Scopus (268) Google Scholar]. However, these comparisons are made among different experimental systems and conditions (e.g., rat hippocampus CA1 pyramidal cells in cultured slices [30Meyer D. et al.Balance and stability of synaptic structures during synaptic plasticity.Neuron. 2014; 82: 430-443Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 31Bosch M. et al.Structural and molecular remodeling of dendritic spine substructures during long-term potentiation.Neuron. 2014; 82: 444-459Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar] and mouse layer 2/3 cortical pyramidal cells in vivo [47Cane M. et al.The relationship between PSD-95 clustering and spine stability in vivo.J. Neurosci. 2014; 34: 2075-2086Crossref PubMed Scopus (137) Google Scholar, 49Gray N.W. et al.Rapid redistribution of synaptic PSD-95 in the neocortex in vivo.PLoS Biol. 2006; 4: e370Crossref PubMed Scopus (268) Google Scholar]). The fluctuations observed in the latter studies represent the sum of both activity-dependent and -independent processes. As a step toward separating their respective contributions, the effects of suppressing activity were examined. Such experiments (in culture) [17Yasumatsu N. et al.Principles of long-term dynamics of dendritic spines.J. Neurosci. 2008; 28: 13592-13608Crossref PubMed Scopus (216) Google Scholar, 54Dvorkin R. Ziv N.E. Relative contributions of specific activity histories and spontaneous processes to size remodeling of glutamatergic synapses.PLoS Biol. 2016; 14e1002572Crossref PubMed Scopus (27) Google Scholar] have shown that suppressing all spontaneous activity reduces the magnitude of glutamatergic synapse size fluctuations, but only by a factor of about two. Interestingly, little to no change was observed for GABAergic synapses [6Rubinski A. Ziv N.E. Remodeling and tenacity of inhibitory synapses: relationships with network activity and neighboring excitatory synapses.PLoS Comput. Biol. 2015; 11e1004632Crossref PubMed Scopus (20) Google Scholar, 40Schuemann A. et al.Structural plasticity of GABAergic axons is regulated by network activity and GABAA receptor activation.Front. Neural Circuits. 2013; 7: 113Crossref PubMed Scopus (27) Google Scholar]. A more direct estimate of the relative contributions is obtained by comparing pairs of synapses formed between the same axons and dendrites (see Figure 2 for an illustration of this approach). Such pairs share common activation histories that should drive similar remodeling in the two synapses. Conversely, size or remodeling differences between synapses belonging to the same pair would