Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation

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Abstract

A novel property of hippocampal LTP,  `variable persistence', has recently been described that is, we argue, relevant to the role of LTP in information storage. Specifically, new results indicate that a particular pattern of synaptic activation can give rise, either to a relatively short-lasting LTP, or to a longer-lasting LTP as a function of the history of activation of the neuron.  This has led to the idea that the induction of LTP is associated with the setting of a `synaptic tag' at activated synapses, whose role is to sequester plasticity-related proteins that then serve to stabilize temporary synaptic changes and so extend their persistence. In this article, we outline the synaptic tag hypothesis, compare predictions it makes with those of other theories about the persistence of LTP, and speculate about the cellular identity of the tag. In addition, we outline the requirement for aminergic activation to induce late LTP and consider the functional implications of the synaptic tag hypothesis with respect to long-term memory.

Section snippets

Early LTP and late LTP

Much progress has been made in elucidating the cellular mechanisms that underly the induction and early expression of LTP ([5]), but less is known about its maintenance. A key observation is that the extended persistence of NMDA-receptor-dependent LTP beyond about four hours is critically dependent on protein and mRNA synthesis6, 7, 8, 9, 10, 11, 12, 13, 14. LTP is, therefore, divided into an `early' form whose induction is unaffected by protein-synthesis inhibitors, and a `late' form that is

Protein trafficking and the synaptic tag hypothesis

Although the identity of the proteins responsible for stabilizing LTP has not been established, its occurrence raises the following fundamental question: given that macromolecule synthesis occurs mainly in the cell body[23], how do these proteins find their way through the dendrites to the appropriate synapses where the stabilization of early LTP is required? In general, there are considered to be four hypotheses about how the synapse specificity of late LTP could be achieved (see also 11, 24,

Variable persistence: the induction of protein-synthesis-dependent LTP during the inhibition of protein synthesis

Frey and Morris[14] conducted the following test of the synaptic tag idea. Using hippocampal slices in vitro, two independent pathways were activated with low-frequency test pulses and each tetanized once (Fig. 2F). First, pathway S1 was tetanized with a strong tetanus to induce late LTP. Thirty-five minutes later, anisomycin was added to the test chamber to shut down protein synthesis, which happened quickly9, 32. Then, 25 minutes after that, with protein synthesis arrested, pathway S2 was

The identity of the tag

What is the molecular identity of the putative synaptic tag? One possibility is a change in spine-neck diameter. If synapses displaying early LTP had wider neck diameters than synapses that had not recently been potentiated, access to the synaptic apposition zone might then be easier for the large macromolecules that we assume are responsible for stabilizing LTP. Simulation studies have revealed that although changes in spine shape are not responsible for changes of synaptic efficacy, branching

Plasticity-related proteins and the role of aminergic innervation

LTP experiments typically have a three-phase design: a low-frequency test-pulse baseline, a brief period of high-frequency stimulation (or, with intracellular recording, the pairing of pre- and postsynaptic activation) followed by a second period of test pulses. We have all got so used to this arrangement that it is easy to overlook the more likely situation, in vivo, where LTP of individual synapses is probably happening frequently. The synaptic population of an individual CA1 cell is likely

Functional implications

Our concept of synaptic tagging has been developed in hippocampal slices in vitro. Future experiments should explore whether or not the concept is applicable to the intact animal and of any relevance to memory formation and learning. Two-pathway experiments of the kind we have used[14] need to be conducted in vivo, preferably in freely-moving animals. However, an indication that synaptic tagging might occur in the intact organism has already come from experiments investigating the influence of

Concluding remarks

The synaptic tag hypothesis allows us to think about the properties of LTP in a new way. In thinking about associativity, input specificity, rapid induction and persistence, we should now recognize that persistence can be variable. The usual way of thinking about associativity is in terms of the heterosynaptic interaction of two or more inputs, over a short time scale (less than one second), mediated via the voltage dependence of the NMDA receptor[70]. The synaptic tag idea points to a

Acknowledgements

This work was supported by grants of German Bundesministerium für Bildung und Forschung and of Kultusministerium of Land Saxony-Anhalt held by UF, and an MRC Programme Grant and an HFSP Grant held by RGMM.

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