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The Synaptic Tagging and Capture Hypothesis

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The Synaptic Tagging and Capture Hypothesis REVIEWS Making memories last: the synaptic tagging and capture hypothesis Roger L. Redondo*‡ and Richard G. M. Morris* Abstract | The synaptic tagging and capture hypothesis of protein synthesis-dependent long-term potentiation asserts that the induction of synaptic potentiation creates only the potential for a lasting change in synaptic efficacy, but not the commitment to such a change. Other neural activity, before or after induction, can also determine whether persistent change occurs. Recent findings, leading us to revise the original hypothesis, indicate that the induction of a local, synapse-specific ‘tagged’ state and the expression of long-term potentiation are dissociable. Additional observations suggest that there are major differences in the mechanisms of functional and structural plasticity. These advances call for a revised theory that incorporates the specific molecular and structural processes involved. Addressing the physiological relevance of previous in vitro findings, new behavioural studies have experimentally translated the hypothesis to learning and the consolidation of newly formed memories. 13 Engram Memories are made as we go about our daily life: what being revealed . The cellular component concerns the The concept, first introduced in event has happened, with whom, where and when. Most more immediate determinants of synaptic strength and the nineteenth century, to memories fade, whereas others last. What determines persistence that are triggered within individual neurons define the physical entity in the whether we remember or not? A longstanding theory is in the minutes and hours after memory encoding. The brain that stores information that the physical substrate of ‘engrams’ or ‘traces’ for long- synaptic tagging and capture (STC) hypothesis, of which over time and later enables memories to be expressed. term memory (LTM) is an alteration in the efficacy of syn- we here provide a major revision, focuses mainly on the apses within relevant neural networks1–4. Different types cellular component of consolidation. Memory encoding of learning (declarative, spatial, emotional, procedural and Various predictions derive from this dual framework, The physiological process by so on) are mediated by distinct brain networks. Some of one of which is that the temporal persistence of synap- which patterns of neural activity result in the creation (that is, these networks involve a distributed associative storage tic potentiation (or depression) must be crucial for the 14 encoding) of a state somewhere system in which specific memory traces are not stored persistence of memory . Excitatory, glutamatergic syn- in the brain that can be within individual neurons, still less at a single synaptic apses in the hippocampus play a key part in learning characterized as an engram. location, but are distributed in an overlapping manner and memory, and their activation triggers diverse intra- across multiple neurons and synapses5. cellular signal transduction cascades and somatic and There are many determinants of the persistence of dendritic protein synthesis. Collectively, these processes *Laboratory for Cognitive such engrams. However, a common thread is that memory alter synapses biophysically and structurally, stabilizing Neuroscience, Centre for encoding Cognitive and Neural and initial storage are followed by a ‘consolidation’ a new (possibly temporary) level of synaptic strength. Systems, The University of process that, if activated, enables traces to become The stabilization process enables synapses to retain their Edinburgh, 1 George Square, stabilized, although not necessarily immutable6–9. strength for long periods despite continual turnover of Edinburgh EH8 9JZ, UK. There are both cellular and systems components of their constituent proteins. ‡Present address: Picower Institute for Learning and memory consolidation, and of the memory-updating There is good evidence for this way of thinking about 7,8 Memory, Massachusetts process called ‘reconsolidation’ . The systems compo- the consolidation of synaptically mediated memory, but Institute of Technology (MIT), nent involves dynamic interactions between, for exam- we argue below that it overlooks a key aspect of memory 43 Vassar Street, Cambridge, ple, network activation of hippocampal and neocortical processing. Specifically, stabilization also depends upon Massachusetts, 02139, USA. neurons in the creation or updating of lasting engrams. the recent history of neuronal activity and immediate Correspondence to R.G.M.M. e-mail: The neurobiological mechanisms underlying the deter- future activity, both of which can be independent of [email protected] minants of systems consolidation (which include the neural activity that occurs during or is triggered by doi:10.1038/nrn2963 passage of time10,11 and prior knowledge12) are gradually encoding itself. This extension of the time window that NATURE REVIEWS | NEUROSCIENCE VOLUME 12 | JANUARY 2011 | 17 © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS C D E *QYCTGUVTWEVWTCN 5VTQPI 9JCVCTGVJGOGEJCPKUOU 9GCM 9GCM CPFHWPVKQPCN VGVCPK\CVKQP QHUNQYQPUGVU[PCRVKE VGVCPK\CVKQP VGVCPK\CVKQP RNCUVKEKV[FKȭGTGPV! RNCUVKEKV[! 5QOC +UVCIUGVVKPIPGEGUUCT[ HQTVJGGZRTGUUKQPQH 6CIUGVVKPI 9JCVUKIPCNU 6CIUGVVKPI .62CPFXKEGXGTUC! 6CIUGVVKPI VQVJGPWENGWU! 6CIIGF U[PCRUG *QYKUVCIIKPI UWUVCKPGF! O40# 242ECRVWTG242ECRVWTG 242UPQVCXCKNCDNG 9JCVKUVJGTQNG *QYHCTCNQPIVJGFGPFTKVKE 242 QHFGPFTKVKEO40#! VTGGECP56%QEEWT! *QYFQGUFGRQVGPVKCVKQP CȭGEVVCIIKPICPFECRVWTG! *QYKU56%KP.62 FKȭGTGPVHTQO56% KP.6&! ..62 ..62 4GVWTPVQ *QYKU56%TGNGXCPVVQ DCUGNKPG NGCTPKPICPFOGOQT[! Figure 1 | The synaptic tagging and capture (STC) hypothesis and its challenges. a | As originally proposed, the strong tetanization of one synaptic pathway leads to two dissociable events: local tag setting0CVWT andG4G theXKGYU synthesis^0GWTQUEKGPEG of diffusible plasticity-related proteins (PRPs). The PRPs are then captured by tagged synapses, and this is necessary for the maintenance of late-long-term potentiation (L-LTP). b | A weakly stimulated set of synapses that has access to the PRPs will also succeed in maintaining L-LTP. c | Without the availability of PRPs, the receptive state (tagging) of the synapses will fade and L-LTP will not be sustained. Challenges to the basic model are highlighted. LTD, long-term depression. determines memory consolidation — both backwards The core concepts of the STC hypothesis and forwards — enables the synthesis and distribution A core concept of the STC hypothesis17,18 is that mem- of plasticity-related proteins that is induced by other ory encoding creates the potential for LTM but is non- activity to be captured by so called ‘synaptic tags’ that commital with respect to whether persistent memory will are set at the time of memory encoding. Synaptic tags, actually occur (FIG. 1). For experimental neuroscientists described in detail below, are local molecular changes — be they physiologists doing brain slice work on long- at synapses that mark synaptic plasticity as having term potentiation (LTP) or behavioural scientists study- occurred. From a computational perspective, the con- ing learning in laboratory animals — it is natural to think cept provides a new way of thinking about synaptic of ‘memory formation’ in one’s chosen model as a discrete potentiation in which the various ‘states’ of a synapse set of interacting events triggered at a particular moment reflect both the current level of synaptic strength and in time. Thus, strong tetanization, given in the form the potential of the synapse for lasting changes in of a train of high-frequency pulses, increases the ampli- strength15,16. tude of excitatory postsynaptic potentials (EPSPs) before In this Review, we outline the conceptual frame- our eyes; similarly, an animal makes a choice in a behav- work of the STC hypothesis, discuss experimental chal- ioural learning task, receives reward or punishment for lenges to the original hypothesis and introduce a revised doing so, and shows changes in its behaviour that reflect theory. We also consider new behavioural studies that such learning. have explored the relevance of the STC hypothesis to Reality is otherwise, with memorable events learning and the consolidation of newly formed memo- happening before and after others such that, in daily life ries. This new, overarching framework considers memory as opposed to the laboratory, streams of neural activity formation as an ongoing process influenced by its past, are being processed continuously. The memorability of present and future. This unique approach allows a an apparently isolated episode is likely to be concurrently broader and fuller understanding of the likely molecular affected by what has happened, or will happen soon. By underpinnings of the engram. contrast, if memory consolidation mechanisms were 18 | JANUARY 2011 | VOLUME 12 www.nature.com/reviews/neuro © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS automatically triggered by stimulus events and deter- first two mechanisms in the process of LTP — synaptic mined solely by the characteristics of the stimuli (such potentiation and tag setting — were assumed to be trig- as their strength or repetition19), the declarative and pro- gered simultaneously, and tag decay and the decline of cedural memory systems of the brain would be simul- potentiation to baseline were thought to follow an iden- taneously handling numerous consolidation cascades at tical time course. New findings, discussed below, ques-
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