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  • Review Article
  • Published:

Making memories last: the synaptic tagging and capture hypothesis

Key Points

  • The fate of a memory is not determined at the time of encoding, and this can be explained by the susceptibility of synaptic plasticity to modulation around the time of induction.

  • The synaptic tagging and capture (STC) hypothesis explains this by dissociating synapse-specific tagging from diffusible plasticity-related products (PRPs) — that is, proteins and mRNAs.

  • Recent findings suggest that the induction of the tagged state can be independent of the expression of long-term potentiation (LTP) itself, and this can be explained by differences in the mechanisms of structural and functional plasticity. In this way, experiments targeting structural plasticity block tagging while allowing the expression of LTP.

  • Taking this into account, the STC can contribute to the understanding of a series of electrophysiological and behavioural phenomena ranging from synaptic plasticity to reconsolidation. For example, slow-onset plasticity is explained through tagging without immediate expression, whereby LTP develops as PRPs are captured by non-potentiated but tagged synapses.

  • Behaviourally, weak encoding protocols achieve long-term memory if PRPs are made available by an unrelated event before or after encoding.

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.

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Figure 1: The synaptic tagging and capture (STC) hypothesis and its challenges.
Figure 2: The dissociation of LTP expression and synaptic tagging.
Figure 3: A distinction between structural and functional plasticity.
Figure 4: The revised STC hypothesis — molecular events associated with induction of E-LTP and L-LTP.
Figure 5: Synaptic tagging and capture.
Figure 6: Behavioural correlates of synaptic tagging and capture.

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Acknowledgements

This work was supported by grants from the UK Medical Research Council, the Volkswagen Stiftung and the Human Frontiers Science Program. We are grateful to many colleagues for discussion of these ideas, including T. Bonhoeffer, R. Fonseca, H. Bito, H. Okuno, M. van Rossum and A. Barrett, and our colleagues in the Laboratory for Cognitive Neuroscience. R.L.R. is now at the Picower Institute, MIT. R.G.M.M. is a Royal Society/Wolfson Professor at the University of Edinburgh. Special thanks to C. Wiedemann for the invitation and encouragement to write this Review.

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Correspondence to Richard G. M. Morris.

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Supplementary information

Supplementary information S1 (movie)

E-LTP: Due to the lack of PRPs, a synapse that has undergone both functional and structural plasticity returns to its basal state. (SWF 26 kb)

Supplementary information S2 (movie)

L-LTP: Following structural and functional plasticity changes, PRPs find a receptive synapse to which they can contribute. (SWF 27 kb)

Supplementary information S3 (figure)

Three challenges to STC explained. (PDF 207 kb)

Supplementary information S4 (movie)

Tag block leads to E-LTP: The inhibition of structural plasticity still allows for the functional expression of E-LTP but this is short-lasting as the available PRPs are not allowed to contribute to the maintenance of L-LTP. (SWF 69 kb)

Supplementary information S5 (movie)

Slow onset plasticity: Even without the immediate expression of LTP, structural plasticity makes the synapse receptive to PRPs allowing LTP to develop gradually. (SWF 22 kb)

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FURTHER INFORMATION

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Glossary

Engram

The concept, first introduced in the nineteenth century, to define the physical entity in the brain that stores information over time and later enables memories to be expressed.

Memory encoding

The physiological process by which patterns of neural activity result in the creation (that is, encoding) of a state somewhere in the brain that can be characterized as an engram.

Two-pathway LTP experiment

An experiment that studies two independent sets of synapses that converge onto the same cell.

Cross-capture experiment

A two-pathway experiment in which a weak, early-long-term potentiation (E-LTP)-inducing protocol delivered to one pathway is rescued into late-LTP (L-LTP) if a strong, L-LTD-inducing protocol is delivered to the other pathway at around the same time. The phenomenon is reciprocal, as rescue of E-LTD into L-LTD occurs when another pathway experiences a strong, L-LTP-inducing protocol.

Place cell

A neuron that exhibits a high rate of firing when an animal is at a specific location in an environment.

PSD slot

A group of proteins in the postsynaptic density (PSD) that is capable of binding AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole) receptors.

Immediate early genes

Genes whose expression is upregulated transiently but quickly in response to a specific stimulus, such as memory encoding.

Competitive maintenance

The theory explaining the observation that two pathways already expressing long-term potentiation (LTP) will compete for scarce plasticity-related products when they are further tetanized after a period of protein synthesis inhibition during the maintenance phases of LTP.

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Redondo, R., Morris, R. Making memories last: the synaptic tagging and capture hypothesis. Nat Rev Neurosci 12, 17–30 (2011). https://doi.org/10.1038/nrn2963

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