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Long-term depression in the CNS

Key Points

  • Long-term depression (LTD) encompasses a family of synaptic plasticity mechanisms that can be triggered by the synaptic or pharmacological activation of glutamate receptors — in particular NMDARs (N-methyl-D-aspartate receptors) and metabotropic glutamate receptors (mGluRs) — or receptors for other neurotransmitters.

  • LTD is expressed by a long-lasting decrease in the efficiency of synaptic transmission, in particular synaptic transmission that is mediated by the synaptic activation of AMPARs (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors). It may involve presynaptic and postsynaptic mechanisms.

  • Complex signalling cascades link the induction of LTD to its expression. The cascades involve Ca2+ sensors, protein–protein interactions, protein kinases and phosphatases, proteases and other signalling molecules.

  • Historically, a lack of specific inhibitors for LTD has hampered efforts to specify its functional role. The recent development of interference peptide inhibitors targeted at the carboxyl tail of the AMPAR subunit GluA2 subunit has proven important in specifying the functional roles of LTD.

  • LTD has diverse roles in cognition, particularly in some forms of learning and memory and in circumstances in which a flexible response is required.

  • LTD also seems to be involved in pathological states, including drug addiction, mental retardation and neurodegenerative diseases such as Alzheimer's disease.

Abstract

Long-term depression (LTD) in the CNS has been the subject of intense investigation as a process that may be involved in learning and memory and in various pathological conditions. Several mechanistically distinct forms of this type of synaptic plasticity have been identified and their molecular mechanisms are starting to be unravelled. Most studies have focused on forms of LTD that are triggered by synaptic activation of either NMDARs (N-methyl-D-aspartate receptors) or metabotropic glutamate receptors (mGluRs). Converging evidence supports a crucial role of LTD in some types of learning and memory and in situations in which cognitive demands require a flexible response. In addition, LTD may underlie the cognitive effects of acute stress, the addictive potential of some drugs of abuse and the elimination of synapses in neurodegenerative diseases.

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Figure 1: Signalling mechanisms involved in NMDAR-dependent LTD.
Figure 2: Signalling mechanisms involved in mGluR-LTD(A).
Figure 3: Molecular interactions between long-term potentiation and long-term depression.
Figure 4: Schematic summary of the use of interference peptides to study the physiological functions of LTD.

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Acknowledgements

We would like to thank C. A. Thai for editorial assistance with this manuscript. G.L.C. and S.P. are supported by the Medical Research Council. G.L.C. is a Royal Society–Wolfson Merit Award Holder and a World Class University International Scholar. J.G.H. is supported by the Natural Sciences and Engineering Research Council of Canada, National Alliance for Research on Schizophrenia and Depression, Saskatchewan Health Research Foundation, and Canada Foundation for Innovation. Y.T.W. is supported by the Canadian Institutes for Health Research and is also a Howard Hughes Medical Institute International Research Scholar and the Heart and Stroke Foundation of British Columbia and Yukon Chair in Stroke Research.

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Correspondence to Graham L. Collingridge, Stephane Peineau, John G. Howland or Yu Tian Wang.

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Involvement of NMDA and mGlu receptors in homosynaptic AMPA-LTD induction at various synapses of mammalian CNS (selected references are indicated) (PDF 363 kb)

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FURTHER INFORMATION

Université Paris 7, Unité 676

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Glossary

Long-term potentiation (LTP)

A long-lasting (hours or days) increase in the synaptic response of neurons to stimulation of their afferents following a brief patterned stimulus (for example, 1 second stimulation at 100 Hz).

Long-term depression (LTD)

A long-lasting decrease in the synaptic response of neurons to stimulation of their afferents following a long patterned stimulus (for example, 15 minutes of stimulation at 1 Hz).

Low-frequency stimulation (LFS)

Stimulation of synapses by a train of electric pulses delivered by an electrode at a frequency that usually never exceeds 10 Hz on the afferent fibres.

Single-shock low-frequency stimulation

A version of low-frequency stimulation in which the train of pulses used in the stimulation protocol is constituted of single pulses.

Paired-pulse low-frequency stimulation

A version of low-frequency stimulation in which the train of pulses used in the stimulation protocol is constituted of a pair of pulses (usually at 20 Hz).

Retrograde messenger

A biological signal released by the postsynaptic side of the synapse to induce a modification on the presynaptic side of the synapse. The most common retrograde messengers are nitric oxide and endocannabinoids.

Clathrin-mediated endocytosis

A process in which vesicles are formed using a complex of proteins that are mainly associated with the cytosolic protein clathrin in order to internalize molecules from the extracellular space and regulate membrane composition by removing specific membrane proteins such as AMPARs.

Scaffolding proteins

Proteins that can link with several other proteins and lipids and thus position proteins that are involved in signalling pathways close to their targets.

Reversal learning

A task in which participants are trained to respond differentially to two stimuli under conditions of reward and punishment (or non-reward). The participants therefore learn to change their behaviour when the reward values are reversed.

Behavioural flexibility

Alterations in well-established behaviours in response to changes in the environment.

Haloperidol

An antipsychotic medication with dopamine receptor antagonist properties, particularly in relation to the dopamine receptor 2 subtype.

Extinction

Reduced responses to a previously conditioned cue when the cue is presented repeatedly in the absence of the previously paired aversive or appetitive stimulus.

ZIP peptide

A cell-permeable inhibitor of the persistently active kinase protein kinase C isoform M ζ (PKMζ).

Vestibulo-ocular reflex

Reflex movements of the eyes that are elicited by vestibular stimulation. These movements keep the retinal image stable, preventing degradation of visual processing.

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Collingridge, G., Peineau, S., Howland, J. et al. Long-term depression in the CNS. Nat Rev Neurosci 11, 459–473 (2010). https://doi.org/10.1038/nrn2867

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