Synaptic tagging — who's it?

Key Points

  • Long-term changes in synaptic efficacy commonly require gene expression and protein translation. However, this type of plastic change can be restricted to just a few of the contacts that a given neuron receives. How can cell-wide processes such as transcription be restricted to a small subset of synapses? An idea that has been put forward to answer this question is that of the 'synaptic tag', which marks synapses that are to experience the plastic change such that only those contacts with the tag can use the products of transcription.

  • Studies in Aplysia cell cultures and rat hippocampal slices have provided good evidence for the existence of a synaptic tag. In both cases, once a neuron has been stimulated to undergo long-term, transcription-dependent synaptic plasticity, the cell can use stimuli that normally produce transient changes in synaptic strength to induce more persistent changes at a different set of synapses. This capability persists only within a discrete time window, during which the putative tag can capture the products of gene expression that are induced by strong activity elsewhere in the neuron.

  • Any candidate synaptic tag should fulfil several criteria. First, it should be spatially restricted. Second, it should be time-limited and reversible. Third, it should be able to interact with cell-wide molecular events that occur after strong stimulation. So, from a broad perspective, anything that provides a spatially restricted trace of activity is a candidate synaptic tag.

  • Persistently active kinases, adhesion molecules, the actin network and ion channels have been put forward as possible synaptic tags. Similarly, the local translation and degradation of proteins have also been considered as possible mechanisms to tag active synapses. As the evidence in support of all of these possibilities is good, it is probable that neurons do not use a single synaptic tag to mark synapses, but a wide variety of them.

  • The identity of the transcriptional products that interact with the tag remains unknown. Although a couple of candidates has been put forward, their precise identification constitutes one of the main challenges for this field.

Abstract

A synaptic tag transiently marks a synapse after activation in a way that allows the local recognition of transcriptional products to effect an enduring change in transmission efficiency. The idea of the synaptic tag as a single molecule might be misguided; instead, a process such as activation of local translation or cytoskeletal reorganization could mark a synapse. A change of this nature might be modulated directly or indirectly by transcriptional products that, for example, modulate translational activity, mRNA stability or protein degradation, or are ensconced in a cytoskeletal configuration, and thereby lead to long-term changes in synaptic strength.

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Figure 1: Synaptic tagging in cultures of sensory and motor Aplysia neurons.
Figure 2: Synaptic tagging in rodent hippocampal neurons.
Figure 3: A model of synaptic tagging in which activity-dependent effects on translation serve as the tag.

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Acknowledgements

We would like to thank M. Barad, M. Mayford, R. Moccia, E. Schuman, W. Sossin and O. Steward for their insightful comments on the manuscript.

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DATABASES

LocusLink

actin

AMPA receptors

Arc

BDNF

cadherins

CaMKII

β-catenin

δ-catenin

CREB

mGluR5

NCAM

neurotrophin 3

NMDA receptors

PKA

PKM-ζ

PSD95

TrkB

ubiquitin carboxy-terminal hydrolase

FURTHER INFORMATION

Encyclopedia of Life Sciences

learning and memory

long-term potentiation

protein phosphorylation and long-term synaptic plasticity

protein synthesis and long-term synaptic plasticity

Glossary

SCHAFFER COLLATERALS

Axons of the CA3 pyramidal cells of the hippocampus that form synapses with the apical dendrites of CA1 neurons.

HOMER

A protein of the postsynaptic density that can interact with metabotropic glutamate receptors, regulating their membrane insertion and their interaction with other postsynaptic proteins.

UBIQUITIN

A molecule that is attached to lysine residues of other proteins, often as a tag for their rapid cellular degradation by the proteasome.

PROTEASOME

A protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.

HYPOMORPH

A mutant that expresses less than the normal amount of a given gene product.

ADHERENS JUNCTION

A cell–cell junction also known as zonula adherens, which is characterized by the intracellular insertion of microfilaments. If intermediate filaments are inserted in lieu of microfilaments, the resulting junction is referred to as a desmosome.

PHOTOCONDUCTIVE STIMULATION

A method whereby light can be used to stimulate the activity of subpopulations of synapses in vitro. Cells are cultured on a silicon chip and light is applied to single neurons. As the conductivity of silicon changes in response to light, it is possible to pair local illumination of single neurons with subthreshold electrical stimulation of the whole culture. So, the stimulus intensity will reach threshold for activation solely in the illuminated cell.

INTERNAL RIBOSOME ENTRY SITE

A sequence that is inserted between the coding regions of two proteins and allows efficient assembly of the ribosome complex in the middle of a transcript, leading to translation of the second protein.

MULTIPHOTON MICROSCOPY

A form of microscopy in which a fluorochrome that would normally be excited by a single photon is stimulated quasi-simultaneously by several photons of lower energy. Under these conditions, fluorescence increases as a function of the square of the light intensity, and decreases approximately as the square of the distance from the focus. Because of this behaviour, only fluorochrome molecules near the plane of focus are excited, greatly reducing light scattering and photodamage of the sample.

MICRORNAS

Tiny transcripts of about 22 nucleotides. The functions of these RNAs remain obscure, although they probably serve as antisense regulators of the translation of other RNAs.

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Martin, K., Kosik, K. Synaptic tagging — who's it?. Nat Rev Neurosci 3, 813–820 (2002). https://doi.org/10.1038/nrn942

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