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A clustered plasticity model of long-term memory engrams

Abstract

Long-term memory and its putative synaptic correlates the late phases of both long-term potentiation and long-term depression require enhanced protein synthesis. On the basis of recent data on translation-dependent synaptic plasticity and on the supralinear effect of activation of nearby synapses on action potential generation, we propose a model for the formation of long-term memory engrams at the single neuron level. In this model, which we call clustered plasticity, local translational enhancement, along with synaptic tagging and capture, facilitates the formation of long-term memory engrams through bidirectional synaptic weight changes among synapses within a dendritic branch.

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Figure 1: The MAPK and mTOR pathways regulate neuronal activity-induced translation.
Figure 2: General translational upregulation, and synaptic tagging and capture, enable synaptic integration in translational activation and capture associativity.
Figure 3: Formation of long-term memory engrams in dispersed plasticity and clustered plasticity models.
Figure 4: Clustered plasticity allows for more efficient action-potential firing during recall compared with dispersed plasticity.

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Acknowledgements

We thank C. Stevens, M. Wilson and members of the Tonegawa laboratory for helpful discussions, and critical reading of and comments on the manuscript. Research was supported by the RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute and grants from the National Institutes of Health (S.T. and R.J.K).

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Correspondence to Susumu Tonegawa.

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Glossary

Antidromic

Conduction of an action potential in the opposite direction to normal — that is, towards the cell soma.

Associativity

When stimulation at one synapse is too weak to induce LTP, the simultaneous strong stimulation of another synapse can be sufficient to trigger LTP at both.

Cooperativity

When multiple synaptic inputs that are individually insufficient to induce LTP (or LTD) can collectively produce a postsynaptic depolarization that is sufficient to trigger LTP (or LTD).

Dedepression

A reversal of LTD by high-frequency synaptic stimulation. Dedepression shares some characteristics with LTP — both are induced by high-frequency stimulation, and both require NMDAR and protein kinase activity. However, there is evidence that LTP and dedepression are different processes.

Depotentiation

A reversal of LTP by low-frequency synaptic stimulation. Depotentiation shares some characteristics with LTD — both are induced by low-frequency stimulation, and both require NMDAR and protein phosphatase activity. However, there is evidence that LTD and depotentiation are different processes.

Engram

A persistent change in the brain that is formed in response to a stimulus, and is the neuronal substrate for a memory (also known as a memory trace).

Immediate-early gene

Genes that are induced within minutes of intense neuronal activity, even in the absence of protein synthesis. They are often induced by behavioural training. Examples include Zif268, c-fos and Arc.

Mammalian target of rapamycin

(mTOR). An evolutionarily conserved kinase, originally found to be stimulated by nutrients, that is a component of one of two key pathways in general translational regulation.

Mitogen-activated protein kinase

(MAPK). Any member of a family of evolutionarily conserved kinases (consisting of multiple isoforms of extracellular signal-regulated kinases, c-Jun N-terminal kinases, p38 MAPKs), originally found to be stimulated by growth factors, that are important in relaying signals from the cell membrane to various parts of a cell, including the nucleus, translational machinery, ion channels and cytoskeleton. The MAPK pathway is one of two key pathways in regulating general translation.

Sharp waves

Large amplitude electroencephalogram potentials that are the result of coherent neuronal discharges observed in the hippocampus and are accompanied by high-frequency (200 Hz) oscillations during certain behavioural states.

Synaptic tag

Stimulated synapses are tagged in a protein synthesis-independent manner to distinguish them from other synapses on the same neuron that have not been activated. This mechanism enables tagged synapses to capture proteins required for, and to express, late-phase forms of plasticity, even when they receive stimuli that would normally result in early-phase forms of plasticity.

Synaptic weight

The relative amplitude of the postsynaptic response that is generated by the activity of the presynaptic neuron (also known as synaptic strength).

Theta-burst stimulation

Rhythmic neural activity with a frequency of 4–8 Hz that is present in several parts of the brain during certain behavioural states.

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Govindarajan, A., Kelleher, R. & Tonegawa, S. A clustered plasticity model of long-term memory engrams. Nat Rev Neurosci 7, 575–583 (2006). https://doi.org/10.1038/nrn1937

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