Synaptic Tagging Research Articles

New frontiers in the study of memory mechanisms

We review recent work on three major lines of memory research: a) the possible role of the protein kinase M-zeta (PKMzeta) in memory persistence; b) the processes of "synaptic tagging and capture" in memory formation; c) the modulation of extinction learning, widely used in the psychotherapy of fear memories under the name of "exposure therapy". PKMzeta is a form of protein kinase C (PKC) that apparently remains stimulated for months after the consolidation of a given memory. Synaptic tagging is a mechanism whereby the weak activation of one synapse can tag it with a protein so other synapses in the same cell can reactivate it by producing other proteins that bind to the tag. Extinction, once mistakenly labeled as a form of forgetting, is by itself a form of learning; through it animals can learn to inhibit a response. We now know it can be modulated by neurotransmitters or by synaptic tagging, which should enable better control of its clinical use.

Behavioral tagging of extinction learning.

Extinction of contextual fear in rats is enhanced by exposure to a novel environment at 1-2 h before or 1 h after extinction training. This effect is antagonized by administration of protein synthesis inhibitors anisomycin and rapamycin into the hippocampus, but not into the amygdala, immediately after either novelty or extinction training, as well as by the gene expression blocker 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole administered after novelty training, but not after extinction training. Thus, this effect can be attributed to a mechanism similar to synaptic tagging, through which long-term potentiation can be enhanced by other long-term potentiations or by exposure to a novel environment in a protein synthesis-dependent fashion. Extinction learning produces a tag at the appropriate synapses, whereas novelty learning causes the synthesis of plasticity-related proteins that are captured by the tag, strengthening the synapses that generated this tag.

Making Synapses Strong: Metaplasticity Prolongs Associativity of Long-Term Memory by Switching Synaptic Tag Mechanisms

One conceptual mechanism for the induction of associative long-term memory is that a synaptic tag, set by a weak event, can capture plasticity-related proteins from a nearby strong input, thus enabling associativity between the 2 (synaptic tagging and capture, STC). So far, STC has been observed for only a limited time of 60 min. Nevertheless, association of weak memory forms can occur beyond this period and its mechanism is not well understood. Here we report that metaplasticity induced by ryanodine receptor activation or synaptic activation of metabotropic glutamate receptors prolongs the durability of the synaptic tag, thus extending the time window for associative interactions mediating storage of long-term memory. We provide evidence that such metaplasticity alters the mechanisms of STC from a CaMKII-mediated (in non-primed STC) to a protein kinase Mzeta (PKMζ)-mediated process (in primed STC). Thus the association of weak synapses with strong synapses in the "late" stage of associative memory formation occurs only through metaplasticity. The results also reveal that the short-lived, CaMKII-mediated tag may contribute to a mechanism for a fragile form of memory while metaplasticity enables a PKMζ-mediated synaptic tag capable of prolonged interactions that induce a more stable form of memory that is resistant to reversal.

Deciphering the molecular rules governing synaptic targeting of the memory-related protein Arc

Neurons express new gene transcripts and proteins upon receiving synaptic inputs, and these events are essential for achieving proper neuronal wiring, adequate synaptic plasticity, and updatable memory. However, the biological impact of new gene expression on input-specific synaptic potentiation remains largely elusive, in part because the cell biological and biochemical mechanisms for synaptic targeting of newly synthesized proteins has remained obscure. A new study investigating the targeting of the memory related protein Arc from the soma to the synapses teases apart a novel “inverse” synaptic tagging mechanism that enables Arc to specifically target the un-potentiated synapses, thereby helping to maintain the contrast of synaptic weight between strengthened and weak synapses.

Molecular Constraints on Synaptic Tagging and Maintenance of Long-Term Potentiation: A Predictive Model

Protein synthesis-dependent, late long-term potentiation (LTP) and depression (LTD) at glutamatergic hippocampal synapses are well characterized examples of long-term synaptic plasticity. Persistent increased activity of protein kinase M ζ (PKMζ) is thought essential for maintaining LTP. Additional spatial and temporal features that govern LTP and LTD induction are embodied in the synaptic tagging and capture (STC) and cross capture hypotheses. Only synapses that have been “tagged” by a stimulus sufficient for LTP and learning can “capture” PKMζ. A model was developed to simulate the dynamics of key molecules required for LTP and LTD. The model concisely represents relationships between tagging, capture, LTD, and LTP maintenance. The model successfully simulated LTP maintained by persistent synaptic PKMζ, STC, LTD, and cross capture, and makes testable predictions concerning the dynamics of PKMζ. The maintenance of LTP, and consequently of at least some forms of long-term memory, is predicted to require continual positive feedback in which PKMζ enhances its own synthesis only at potentiated synapses. This feedback underlies bistability in the activity of PKMζ. Second, cross capture requires the induction of LTD to induce dendritic PKMζ synthesis, although this may require tagging of a nearby synapse for LTP. The model also simulates the effects of PKMζ inhibition, and makes additional predictions for the dynamics of CaM kinases. Experiments testing the above predictions would significantly advance the understanding of memory maintenance.

Inverse Synaptic Tagging of Inactive Synapses via Dynamic Interaction of Arc/Arg3.1 with CaMKIIβ

The Arc/Arg3.1 gene product is rapidly upregulated by strong synaptic activity and critically contributes to weakening synapses by promoting AMPA-R endocytosis. However, how activity-induced Arc is redistributed and determines the synapses to be weakened remains unclear. Here, we show targeting of Arc to inactive synapses via a high-affinity interaction with CaMKIIβ that is not bound to calmodulin. Synaptic Arc accumulates in inactive synapses that previously experienced strong activation and correlates with removal of surface GluA1 from individual synapses. A lack of CaMKIIβ either in vitro or in vivo resulted in loss of Arc upregulation in the silenced synapses. The discovery of Arc's role in "inverse" synaptic tagging that is specific for weaker synapses and prevents undesired enhancement of weak synapses in potentiated neurons reconciles essential roles of Arc both for the late phase of long-term plasticity and for reduction of surface AMPA-Rs in stimulated neurons.

Reward alters specific connections

How does the brain couple a fleeting sensory input to a delayed reward during learning? A study in locusts shows that coincident firing of neurons can 'mark' a neuronal connection for later modulation. See Article p.47 Associative learning is thought to involve synaptic plasticity and neuromodulation, but how neuronal circuits determine which synapses should change when blanketed with a nonspecific reinforcer signal has remained mysterious. Focusing on the locust olfactory system, Stijn Cassenaer and Gilles Laurent now demonstrate that 'spike-timing-dependent plasticity' acts as a synaptic tag, which exclusively labels the synapses that act in response to specific odorants. This primes them for subsequent modification by octopamine, a neuromodulator involved in insect learning and memory. The findings explain how neuromodulators can produce specific circuit effects even though their release is both diffuse and delayed relative to sensory inputs.

Novelty exposure overcomes foot shock-induced spatial-memory impairment by processes of synaptic-tagging in rats

Novelty processing can transform short-term into long-term memory. We propose that this memory-reinforcing effect of novelty could be explained by mechanisms outlined in the "synaptic tagging hypothesis." Initial short-term memory is sustained by a transient plasticity change at activated synapses and sets synaptic tags. These tags are later able to capture and process the plasticity-related proteins (PRPs), which are required to transform a short-term synaptic change into a long-term one. Novelty is involved in inducing the synthesis of PRPs [Moncada D, et al. (2011) Proc Natl Acad Sci USA 108:12937-12936], which are then captured by the tagged synapses, consolidating memory. In contrast to novelty, stress can impair learning, memory, and synaptic plasticity. Here, we address questions as to whether novelty-induced PRPs are able to prevent the loss of memory caused by stress and if the latter would not interact with the tag-setting process. We used water-maze (WM) training as a spatial learning paradigm to test our hypothesis. Stress was induced by a strong foot shock (FS; 5 × 1 mA, 2 s) applied 5 min after WM training. Our data show that FS reduced long-term but not short-term memory in the WM paradigm. This negative effect on memory consolidation was time- and training-dependent. Interestingly, novelty exposure prevented the stress-induced memory loss of the spatial task and increased BDNF and Arc expression. This rescuing effect was blocked by anisomycin, suggesting that WM-tagged synapses were not reset by FS and were thus able to capture the novelty-induced PRPs, re-establishing FS-impaired long-term memory.

Synaptic tagging and capture in the living rat

In isolated hippocampal slices, decaying long-term potentiation (LTP) can be stabilized, and converted to late-LTP lasting many hours, by prior or subsequent strong high-frequency tetanization of an independent input to a common population of neurons—a phenomenon known as ‘synaptic tagging and capture’. Here we show that the same phenomenon occurs in the intact rat. Late-LTP can be induced in CA1 during the inhibition of protein synthesis if an independent input is strongly tetanized beforehand. Conversely, declining early-LTP induced by weak tetanization can be converted into lasting late-LTP by subsequent strong tetanization of a separate input. These findings indicate that synaptic tagging and capture is not limited to in vitro preparations; the past and future activity of neurons plays a critical role in determining the persistence of synaptic changes in the living animal, thus providing a bridge between cellular studies of protein-synthesis-dependent synaptic potentiation and behavioural studies of memory persistence.

Emotional modulation of the synapse

Acute stress and emotional arousal can enhance the consolidation of long-term memories in a manner that is dependent on β -adrenoceptor activation in the basolateral complex of the amygdala (BLA). The BLA interacts with multiple memory systems in the brain to modulate a variety of classes of memory. However, the synaptic mechanisms of this interaction remain unresolved. This review describes the evidence of modulation of memory and synaptic plasticity produced by emotional arousal,stress hormones, and pharmacological or electrophysiological stimulation of the amygdala. The amygdala modulation of local translation and/or degradation of the synaptic plasticity-related proteins, activity-regulated cytoskeletal-associated protein and calcium/calmodulin dependent protein kinase II α , is offered as a potential mechanism for the rapid memory consolidation that is associated with emotionally arousing events. This model shares features with synaptic tagging and the emotional tagging hypotheses.

Mechanisms of dendritic mRNA transport and its role in synaptic tagging

The localization of RNAs critically contributes to many important cellular processes in an organism, such as the establishment of polarity, asymmetric division and migration during development. Moreover, in the central nervous system, the local translation of mRNAs is thought to induce plastic changes that occur at synapses triggered by learning and memory. Here, we will critically review the physiological functions of well-established dendritically localized mRNAs and their associated factors, which together form ribonucleoprotein particles (RNPs). Second, we will discuss the life of a localized transcript from transcription in the nucleus to translation at the synapse and introduce the concept of the 'RNA signature' that is characteristic for each transcript. Finally, we present the 'sushi belt model' of how localized RNAs within neuronal RNPs may dynamically patrol multiple synapses rather than being anchored at a single synapse. This new model integrates our current understanding of synaptic function ranging from synaptic tagging and capture to functional and structural reorganization of the synapse upon learning and memory.

TrkB as a Potential Synaptic and Behavioral Tag

Late-phase long-term potentiation (L-LTP), a cellular model for long-term memory (LTM), requires de novo protein synthesis. An attractive hypothesis for synapse specificity of long-term memory is "synaptic tagging": synaptic activity generates a tag, which "captures" the PRPs (plasticity-related proteins) derived outside of synapses. Here we provide evidence that TrkB, the receptor of BDNF (brain-derived neurotrophic factor), may serve as a "synaptic tag." TrkB is transiently activated by weak theta-burst stimulation (TBS) that induces only early-phase LTP (E-LTP). This TrkB activation is independent of protein synthesis, and confined to stimulated synapses. Induction of L-LTP by strong stimulation in one synaptic pathway converts weak TBS-induced E-LTP to L-LTP in a second, independent pathway. Transient inhibition of TrkB around the time of weak TBS to the second pathway diminished L-LTP in that pathway without affecting the first one. Behaviorally, weak training, which induces short-term memory (STM) but not LTM, can be consolidated into LTM by exposing animals to novel but not familiar environment 1 h before training. Inhibition of TrkB during STM training blocked such consolidation. These results suggest TrkB as a potential tag for synapse-specific expression of L-LTP and LTM.

Synaptic tagging and capture: a bridge from molecular to behaviour

Hippocampal plasticity is now widely accepted as being the substrate for episodic memory formation. More specifically, several studies in area CA1 of the hippocampus support the Synaptic Tagging and Capture hypothesis (STC) which describes the induction as well as the consolidation phases of synaptic Long-Term Potentiation/Depression (LTP/D) (for a review see [1]). In this framework, initial changes in the synaptic weights require an external signal, sometimes called 3rd factor, in order to persist over time. This maintenance signal, comparable to the reward of reinforcement learning theory, is non local and leads to associative effects, i.e. synaptic modifications induced by a weak LTP/D event can be rescued by a strong event happening closely in time. Recently, new experimental paradigms corresponding to a behavioural analog of STC have been developed [2,3]. In these setups, Long-Term Memory (LTM) of rodents is probed in different contexts in order to determine how weak versus strong stimuli, as well as open field exploration, influence the lifetime of the memory trace. In the case of novel environment exploration, similar associative effects can be observed as in CA1 slices measurements, where an independent but behaviourally relevant stimulus can help maintain an otherwise decaying memory trace. We propose a simple model network of the medial temporal lobe to bridge the two concepts (LTP/D and LTM) within the framework of STC. The model consists of rate nodes and connectivity patterns inspired from the hippocampus and the lateral amygdala. In order to simulate initial storage and longer temporal evolution of spatial or emotional memory, we implement hippocampal plasticity with a rate version of the Tag-Trigger-Consolidation (TagTriC) model [4], developed to reproduce induction and maintenance of LTP/D in CA1. Finally animal behaviour is derived from elementary statistics of decision units within the network. Simulation results show that the functional properties of TagTriC transpose to this behavioural paradigm. Moreover, the model was able to explain an interference observed when the rescuing event, e.g. open field exploration, occurs too close to the memory encoding event. Responsible for this interference is a resetting of the plastic modifications induced within the same network parts when active consecutively in different contexts. This interaction unfolds naturally from our modified TagTriC consistent with tag resetting in vitro[5]. This work intends to make a first step towards integration of different levels, functional plasticity and behaviour, of a more general theory of memory. It supports the tagging and capture hypothesis as a basic building block for episodic memory.

A unified computational model of the genetic regulatory networks underlying synaptic, intrinsic and homeostatic plasticity

It is well established that the phenomena of synaptic, intrinsic and homeostatic plasticity are mediated – at least in part – by a multitude of activity-dependent gene transcription and translation processes [1-3]. Various isolated aspects of the complex genetic regulatory network (GRN) underlying these interconnected plasticity mechanisms have been examined previously in detailed computational models [4,5]. However, no study has yet taken an integrated, systems biology approach to examining the emergent dynamics of these interacting elements over longer timescales. Here, we present theoretical descriptions and kinetic models of the principle mechanisms responsible for synaptic and neuronal plasticity within a single simulated Hodgkin-Huxley neuron. We describe how intracellular Calcium dynamics and neural activity mediate synaptic tagging and capture (STC), bistable CaMKII auto-phosphorylation, nuclear CREB activation via multiple converging secondary messenger pathways, and the activity-dependent accumulation of immediate early genes (IEGs) controlling homeostatic plasticity. We then demonstrate that this unified model allows a wide range of experimental plasticity data to be replicated. Furthermore, we describe how this model can be used to examine the cell-wide and synapse-specific effects of various activity regimes and putative pharmacological manipulations on neural processing over short and long timescales. These include an examination of the interaction between intrinsic and synaptic plasticity, each dictated by the level of activated CREB; and the differences in functionality generated by STC under regimes of reduced protein synthesis [2,6]. Finally, we discuss how these processes might contribute to maintaining an appropriate regime for transient dynamics in putative cell assemblies within contemporary neural network models of cognitive processing [7,8].

Diversity of neuropsin (KLK8)‐dependent synaptic associativity in the hippocampal pyramidal neuron

Hippocampal early (E-) long-term potentiation (LTP) and long-term depression (LTD) elicited by a weak stimulus normally fades within 90 min. Late (L-) LTP and LTD elicited by strong stimuli continue for >180 min and require new protein synthesis to persist. If a strong tetanus is applied once to synaptic inputs, even a weak tetanus applied to another synaptic input can evoke persistent LTP. A synaptic tag is hypothesized to enable the capture of newly synthesized synaptic molecules. This process, referred to as synaptic tagging, is found between not only the same processes (i.e. E- and L-LTP; E- and L-LTD) but also between different processes (i.e. E-LTP and L-LTD; E-LTD and L-LTP) induced at two independent synaptic inputs (cross-tagging). However, the mechanisms of synaptic tag setting remain unclear. In our previous study, we found that synaptic associativity in the hippocampal Schaffer collateral pathway depended on neuropsin (kallikrein-related peptidase 8 or KLK8), a plasticity-related extracellular protease. In the present study, we investigated how neuropsin participates in synaptic tagging and cross-tagging. We report that neuropsin is involved in synaptic tagging during LTP at basal and apical dendritic inputs. Moreover, neuropsin is involved in synaptic tagging and cross-tagging during LTP at apical dendritic inputs via integrin β1 and calcium/calmodulin-dependent protein kinase II signalling. Thus, neuropsin is a candidate molecule for the LTP-specific tag setting and regulates the transformation of E- to L-LTP during both synaptic tagging and cross-tagging.

Different compartments of apical CA1 dendrites have different plasticity thresholds for expressing synaptic tagging and capture

The consolidation process from short- to long-term memory depends on the type of stimulation received from a specific neuronal network and on the cooperativity and associativity between different synaptic inputs converging onto a specific neuron. We show here that the plasticity thresholds for inducing LTP are different in proximal and distal compartments of apical dendrites. In addition, we show interactions between the proximal and distal compartments of the apical dendrites by providing evidence that even a subthreshold stimulus can activate plasticity-related proteins, such as PKMζ, enabling associativity between two distinct dendritic compartments in apical dendrites to occur.

Synaptic Plasticity: A Unifying Model to Address Some Persisting Questions

ABSTRACTSince it was first observed, synaptic plasticity has been considered as the experimental paradigm most likely to provide us with an understanding of how information is stored in the vertebrate brain. Various types have been demonstrated over these past 45 years, most notably long-term potentiation and long-term depression, and their established characteristics as well as their induction and consolidation requirements are highly indicative of this plasticity being the substrate for skills acquisition and mnemonic engraving. The molecular, biochemical, and structural models that have been proposed in the past, although most accommodate some aspect of synaptic plasticity observations, admittedly cannot offer a universally functional connection between all the phenomena that surround and result in the different modifications of synaptic efficacy. As a result, there are a number of persisting questions. In an attempt toward synthesis, we reviewed the most important studies in the field and believe that we can now propose a unifying Model for synaptic plasticity that can accommodate the experimental evidence and reconcile most of the contradictions. Moreover, from this model emerge potential answers to several unyielding questions, namely, accounting for the induction and expression of long-term depression, identifying the plasticity switch, offering a possible explanation for the sliding modification threshold, and proposing a new mechanism for synaptic tagging.

Cooperation between cholinergic and glutamatergic receptors are essential to induce BDNF‐dependent long‐lasting memory storage

The induction of long-lasting memory storage depends on the behavioral state of humans and animals. This behavioral state is mediated by neuromodulatory systems, like the cholinergic-septum-hippocampal circuit. Cholinergic neurotransmission is known to affect short-term activity-dependent plasticity in various brain areas, including the hippocampus. We could show here that a chemical late-long-term potentiation (LTP) could be induced in the basal dendrites by the coapplication of the cholinergic receptor agonist, carbachol, and the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram at a concentration that by itself has no effect on basal synaptic transmission. This chemical late-LTP was similar to electrical late-LTP in that it is dependent on protein synthesis, cAMP, and NMDA-receptor activation. Occlusion experiments demonstrated that saturation of three tetanus (TET) late-LTP occluded carbachol-rolipram-LTP, indicating that they share similar properties. This cholinergic modulation of LTP in the basal dendrites was mediated by both muscarinic and nicotinic receptors. Carbachol also reinforced an early form of LTP into a long-lasting LTP. Most interestingly, these two forms of LTP could participate in the functional plasticity processes like synaptic tagging and capture (STC). In addition, we studied whether a cooperation between cholinergic and glutamatergic receptors is essential to induce functional synaptic-plasticity. Indeed, we could show that coactivation of acetylcholine/PDE4 inhibition must coincide with the release of glutamate to induce a long-lasting plasticity, showing a functional convergence of the two neuromodulatory systems. Moreover, we could also show that both chemical late-LTP and carbachol-reinforced early-LTP-induced STC processes are mediated by the neurotrophin BDNF.

Metaplasticity governs compartmentalization of synaptic tagging and capture through brain-derived neurotrophic factor (BDNF) and protein kinase Mζ (PKMζ)

Activity-dependent synaptic plasticity is widely accepted to be the cellular correlate of learning and memory. It is believed that associativity between different synaptic inputs can transform short-lasting forms of synaptic plasticity (<3 h) to long-lasting ones. Synaptic tagging and capture (STC) might be able to explain this heterosynaptic support, because it distinguishes between local mechanisms of synaptic tags and cell-wide mechanisms responsible for the synthesis of plasticity-related proteins (PRPs). STC initiate storage processes only when the strength of the synaptic tag and the local concentration of essential proteins are above a certain plasticity threshold. We present evidence that priming stimulation through the activation of metabotropic glutamate receptors substantially increases the "range of threshold" for functional plasticity by producing protein kinase Mζ (PKMζ) as a PRP through local protein synthesis. In addition, our results implicate BDNF as a PRP which is mandatory for establishing cross-capture between synaptic strengthening and weakening, whereas the newly generated PKMζ specifically establishes synaptic tagging of long-term potentiation. Most intriguingly, we show here that STC are confined to specific dendritic compartments and that these compartments contain "synaptic clusters" with different plasticity thresholds. Our results suggest that within a dendritic compartment itself a homeostatic process exists to adjust plasticity thresholds. The range in which these clusters operate can be altered by processes of metaplasticity, which will operate on the cluster independently of other clusters at the same dendrite. These clusters will then prepare the synaptic network to form long-term memories.

Synaptic tagging, evaluation of memories, and the distal reward problem

Long-term synaptic plasticity exhibits distinct phases. The synaptic tagging hypothesis suggests an early phase in which synapses are prepared, or "tagged," for protein capture, and a late phase in which those proteins are integrated into the synapses to achieve memory consolidation. The synapse specificity of the tags is consistent with conventional neural network models of associative memory. Memory consolidation through protein synthesis, however, is neuron specific, and its functional role in those models has not been assessed. Here, using a theoretical network model, we test the tagging hypothesis on its potential to prolong memory lifetimes in an online-learning paradigm. We find that protein synthesis, though not synapse specific, prolongs memory lifetimes if it is used to evaluate memory items on a cellular level. In our model we assume that only "important" memory items evoke protein synthesis such that these become more stable than "unimportant" items, which do not evoke protein synthesis. The network model comprises an equilibrium distribution of synaptic states that is very susceptible to the storage of new items: Most synapses are in a state in which they are plastic and can be changed easily, whereas only those synapses that are essential for the retrieval of the important memory items are in the stable late phase. The model can solve the distal reward problem, where the initial exposure of a memory item and its evaluation are temporally separated. Synaptic tagging hence provides a viable mechanism to consolidate and evaluate memories on a synaptic basis.