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Author's Accepted Manuscript Author’s Accepted Manuscript Synapse-specific stabilization of plasticity processes: The synaptic tagging and capture hypothesis revisited ten years later Angel Barco, Mikel Lopez de Armentia, Juan M. Alarcon PII: S0149-7634(08)00008-0 DOI: doi:10.1016/j.neubiorev.2008.01.002 Reference: NBR 1021 www.elsevier.com/locate/neubiorev To appear in: Neuroscience and Biobehavioral Reviews Received date: 30 October 2007 Revised date: 28 December 2007 Accepted date: 7 January 2008 Cite this article as: Angel Barco, Mikel Lopez de Armentia and Juan M. Alarcon, Synapse-specific stabilization of plasticity processes: The synaptic tagging and capture hypothesis revisited ten years later, Neuroscience and Biobehavioral Reviews (2008), doi:10.1016/j.neubiorev.2008.01.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The STC hypothesis revisited Synapse-specific stabilization of plasticity processes: The synaptic tagging and capture hypothesis revisited ten years later Angel Barco1*, Mikel Lopez de Armentia1 and Juan M. Alarcon2 1Instituto de Neurociencias de Alicante. (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas). Campus de Sant Joan. Apt. 18. Sant Joan d’Alacant. 03550. Alicante, Spain. 2SUNY Downstate Medical Center. 450 Clarkson Ave., Box 25, Brooklyn, NY 11203. * Corresponding author: Angel Barco, Instituto de Neurociencias de Alicante (UMH-CSIC), Campus de Sant Joan, Apt. 18, Sant Joan d’Alacant 03550, Alicante, Spain. Email: [email protected] Running title: The STC hypothesis revisited December 28th, 2007 Accepted manuscript 1 The STC hypothesis revisited Abstract A decade ago, the synaptic tagging hypothesis was proposed to explain how newly synthesized plasticity products can be specifically targeted to active synapses. A growing number of studies have validated the seminal findings that gave rise to this model, as well as contributed to unveil and expand the range of mechanisms underlying late-associativity and neuronal computation. Here, we will review what it was learnt during this past decade regarding the cellular and molecular mechanisms underlying synaptic tagging and synaptic capture. The accumulated experimental evidence has widened the theoretical framework set by the synaptic tagging and capture (STC) model and introduced concepts that were originally considered part of alternative models for explaining synapse-specific LTP. As a result, we believe that the STC model, now improved and expanded with these new ideas and concepts, still represents the most compelling hypothesis to explain late-associativity in synapse-specific plasticity processes. We will also discuss the impact of this model in our view of the integrative capability of neurons and associative learning. 165 words Accepted manuscript Keywords: synaptic plasticity; LTP; associative learning; neuronal computation; synaptic tagging; synaptic capture; metaplasticity 2 The STC hypothesis revisited Contents 1. Description of the biological problem and first evaluation of the hypothesis 2. Refinement and consolidation of the model 2.1 A theoretical framework for late-associativity processes 2.2 Synaptic capture symmetry and the importance of weak-before-strong experiments 2.3 Tags duration and resetting 2.4 Tags for different occasions 2.5 Competitive maintenance 2.6 Cross-tagging and cross-capture 2.7 Cell-wide facilitation, modulation of intrinsic excitability, and other forms of late- associativity 3. Dissecting synaptic capture: Molecular mechanisms 3.1 The tagging process 3.2 Activity-dependent gene expression 3.3 Cellular distribution of new plasticity products 3.4 The capture process 4. Synaptic tagging and neuronal computation 5. Synaptic tagging and associative learning 6. Concluding remarksAccepted manuscript References 3 The STC hypothesis revisited 1. Description of the biological problem and first evaluation of the hypothesis “Because protein synthesis occurs mainly in the cell body, whereas LTP is input specific, the question arises of how the synapse specificity of late LTP is achieved without elaborate intracellular protein trafficking” (Frey and Morris, 1997). Current models to explain how memories are stored rely on stable changes in synaptic weight that modify the activity of specific neuronal circuits. However, the formation of stable memory can be blocked by inhibiting transcription or translation (Barondes and Jarvik, 1964; Flexner et al., 1962; Flexner et al., 1965). The requirement of de novo gene expression and, consequently, the likely participation of the cell nucleus in long-lasting forms of synaptic plasticity impose a critical requirement for any model trying to explain learning-related plasticity: There must be mechanisms that restrict the action of newly transcribed and/or translated gene products to recently active synapses but not to others. To address this biological problem, it was suggested that the persistence of the changes in synaptic strength is mediated by the generation of a transient local synaptic tag at recently activated synapses and by the production of plasticity- related proteins (PRPs) that can be used or captured only at those synapses marked by the tag. This idea, proposed now ten years ago (Frey and Morris, 1997; Martin et al., 1997), was originally referred to us as the synaptic tagging hypothesis, but was later described as the synaptic taggingAccepted and capture (STC) hypothesi manuscripts, a terminology introduced by Kelleher and Tonegawa (Kelleher et al., 2004b) that we also prefer because it emphasizes the existence of two distinct phases in the consolidation of synaptic changes and so facilitates the dissection of the molecular events underlying such changes. Seminal studies in the rat hippocampus (Frey and 4 The STC hypothesis revisited Morris, 1997) and in cultured Aplysia neurons (Martin et al., 1997) provided the first experimental evidence supporting the TSC model. Long-term potentiation (LTP) is the prevalent cellular model for encoding memories in the brain (Martin et al., 2000b). In LTP, as in memory storage, it is possible to distinguish, at least, two stages of storage: there is an early, protein synthesis-independent, short-term stage (E- LTP), which lasts minutes, and a later, long-term stage (L-LTP), which lasts much longer and shares with long-term memory (LTM) the requirement for the synthesis of new mRNA and protein (Frey et al., 1988; Nguyen et al., 1994). In the Schaffer collateral pathway of the rodent hippocampus, high frequency stimulation (HFS), such as a standard 100 Hz tetanus train of 1 sec duration, produces a non-saturating short-lasting LTP, whereas repeated tetanic stimulation elicits L-LTP. Frey and Morris demonstrated that L-LTP could be induced in synapses receiving subthreshold stimulation (i.e. one single train of HFS), which normally only elicits E-LTP, when it was preceded by the stimulation of another set of synapses using suprathreshold stimulation (i.e. three or four trains of HFS) (Figure 1A). They referred to this phenomenon as synaptic capture of L-LTP (Frey and Morris, 1997). A central idea for this model is that the gene products synthesized in response to the induction of the late phase LTP can also be available to other synapses, synapses which must be activated in order to utilize these new gene products. Frey and Morris referred to this local activation process as synaptic tagging. They tested this idea using the inhibitor of Acceptedprotein synthesis anisomycin and manuscript observed that the phenomenon of capture of late phase LTP, contrary to regular L-LTP, was protein synthesis-independent (Frey and Morris, 1997). In parallel, work in branch-specific facilitation in Aplysia neurons revealed indications of the existence of synaptic marking (term originally used in this organism to refer to tagging) and 5 The STC hypothesis revisited capture in invertebrates, suggesting that these processes may be highly conserved through evolution. In sensory-motor neuronal cultures, a simplified model system to study sensitization in Aplysia, a single application of serotonin (5-HT) produces a short-term change in synaptic effectiveness (short-term facilitation or STF), whereas repeated and spaced applications produce changes in synaptic strength that can last for more than a week (long-term facilitation or LTF) (Montarolo et al., 1986). Martin and colleagues found that a single pulse of 5-HT given to one branch produced LTF when preceded by five pulses of serotonin in the opposite branch (Martin et al., 1997). Similarly to the findings in the rat hippocampus, this persistent form of facilitation elicited by one-pulse was independent of protein synthesis suggesting that it relied in the wave of gene expression previously induced by the strong stimulation (Figure 1B). The STC hypothesis provided a compelling explanation for these experimental observations. However, many critical questions regarding STC mechanisms and their physiological role remained unanswered. Are these mechanisms conserved among different organisms and neural types? What is the spatial range and duration of the tag? What are the molecular and
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