Metaplasticity: tuning synapses and networks for plasticity

KEY POINTS * Synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), must be tightly regulated to prevent saturation, which would impair learning.

Metaplasticity mechanisms have evolved to help implement this essential computational constraint. Metaplasticity refers to neural changes that are induced by activity at one point in time

and that persist and affect subsequently induced LTP or LTD. * The activation of NMDA (_N_-methyl-D-aspartate) receptors can cause a persistent reduction in LTP induction and an enhancement

of LTD. These effects are synapse-specific, last tens of minutes and contribute to LTD induction during conventional low-frequency stimulation protocols. The mechanisms of this regulation

are poorly understood, but activation of protein phosphatases and alteration of calcium/calmodulin-dependent protein kinase II function are clear candidates. * Prior activation of group 1

metabotropic glutamate receptors (group 1 mGluRs) facilitates both the induction and the persistence of LTP in the hippocampus. The facilitated induction probably involves depression of

afterhyperpolarizations (AHPs) and trafficking of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors to the extrasynaptic membrane, whereas the facilitated persistence

entails _de novo_ local protein synthesis. * Heterosynaptic metaplasticity that crosses between synapses can also occur. Stimulation of protein synthesis by activity in one set of synapses

can facilitate LTP persistence through a synaptic tag-and-capture process operating at a second set of weakly activated synapses. Heterosynaptic metaplasticity can also be mediated by

altered postsynaptic ion-channel function and retrograde endocannabinoid signalling that reduces transmission at nearby inhibitory GABAergic terminals. * Behaviourally, stress can inhibit

LTP and facilitate LTD through NMDA-receptor-dependent mechanisms. Sensory stimulation or deprivation alters plasticity thresholds in cortical regions, especially during developmental

periods. Reductions in the slow AHP in piriform and hippocampal neurons support the learning of behavioural tasks, suggesting a metaplastic role for this mechanism in controlling

learning-related plasticity thresholds. * The ability to harness metaplasticity mechanisms might contribute to strategies for treating adult amblyopia or the development of therapies aimed

at improving cognition in individuals with neurological disorders. Metaplasticity paradigms also share commonalities with ischaemic preconditioning, so its mechanisms might present targets

for preventing stroke in at-risk individuals. * In conclusion, metaplasticity is a major regulator of plasticity thresholds and therefore has a key role in keeping synapses working in a

range that permits the full expression of plasticity. In turn, this helps to keep networks operating at an appropriate level for information processing and storage. Considerable research is

still needed to clarify the mechanisms that underpin different forms of metaplasticity and their contribution to network dynamics and behavioural learning. ABSTRACT Synaptic plasticity is a

key component of the learning machinery in the brain. It is vital that such plasticity be tightly regulated so that it occurs to the proper extent at the proper time. Activity-dependent

mechanisms that have been collectively termed metaplasticity have evolved to help implement these essential computational constraints. Various intercellular signalling molecules can trigger

lasting changes in the ability of synapses to express plasticity; their mechanisms of action are reviewed here, along with a consideration of how metaplasticity might affect learning and

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PLASTICITOME OF CORTICAL INTERNEURONS Article 30 December 2022 CO-DEPENDENT EXCITATORY AND INHIBITORY PLASTICITY ACCOUNTS FOR QUICK, STABLE AND LONG-LASTING MEMORIES IN BIOLOGICAL NETWORKS

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  Download references ACKNOWLEDGEMENTS Preparation of this Review was assisted by a James Cook Fellowship from the Royal Society of New Zealand. Metaplasticity research in the author's

laboratory has been supported by grants from the Health Research Council of New Zealand, the New Zealand Marsden Fund and the University of Otago Research Committee. I thank M. Bear for many

years of discussion and collaboration on metaplasticity topics. I thank D. Ireland, J. Wagner and E. Quinlan for comments on an earlier version of this manuscript. AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS * Department of Psychology and the Brain Health and Repair Research Centre, University of Otago, BOX 56, Dunedin, 9054, New Zealand Wickliffe C. Abraham Authors *

Wickliffe C. Abraham View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Wickliffe C. Abraham. RELATED LINKS RELATED

LINKS DATABASES OMIM Alzheimer's disease Down syndrome Fragile X-linked mental retardation syndrome Huntington's disease Parkinson's disease FURTHER INFORMATION Wickliffe

Abraham's homepage GLOSSARY * Long-term potentiation (LTP). A long-lasting and activity-dependent increase in synaptic efficacy. Canonically it requires activation of the NMDAR subtype

of glutamate receptors; however, different forms of LTP caused by the activation of other receptor subtypes also occur. * Long-term depression (LTD). The converse of LTP: in LTD there is a

long-lasting and activity-dependent decrease in synaptic efficacy. * Excitotoxicity Cellular toxicity involving the activation of glutamate receptors in the CNS. Excessive activation of

these receptors by high concentrations of glutamate or by neurotoxins leads to cell death. * Tetanus A bout of HFS used to elicit activity-dependent synaptic plasticity. The frequency and

duration of the stimulation varies across protocols. * Uncaging The release of a molecule from a photolabile binding partner known as a cage. Cages typically inhibit the biological activity

of the bound ('caged') molecule. A brief flash of light of the appropriate wavelength can photochemically disrupt the structure of the binding partner and render the now uncaged

molecule biologically active. * Calcium/calmodulin-dependent protein kinase II (CaMKII). A multi-functional serine/threonine kinase that is activated by a Ca2+/calmodulin complex. Once

activated, CaMKII can autophosphorylate, leading to autonomous (Ca2+-independent) activity and calmodulin trapping. The α isoform is a major component of the postsynaptic density and a key

component of the LTP induction process. * Slow afterhyperpolarization (slow AHP). A type of membrane hyperpolarization that can last for seconds. It is mediated by the opening of

Ca2+-dependent K+ channels and is generated in response to the firing of one or more postsynaptic Na+ or Ca2+ action potentials. * G-protein-coupled receptors (GPCRs). A large family of

transmembrane receptors that couple extracellular signalling molecules to an intracellular signalling cascade which they trigger by activating a G protein. * Depotentiation A reversal of LTP

that brings synaptic efficacy to a baseline level. There is growing evidence that this process involves mechanisms that are different to those that mediate LTD. * Antidromic stimulation The

activation of neuronal cell bodies and dendrites by back-propagating action potentials triggered by electrical stimulation of the cells' axons. * Plasticity-related proteins (PRPs).

Proteins that are synthesized in response to synaptic activation or postsynaptic activity and that are necessary for establishing the persistent forms of LTP and LTD. * Back-propagating

action potentials Action potentials that are initiated at the soma or the axon hillock and that propagate back into the dendrites, where they shape the integration of synaptic activity and

influence the induction of synaptic plasticity. * Active zone A portion of the presynaptic membrane that faces the postsynaptic density across the synaptic cleft. It is the site of synaptic

vesicle clustering and docking and resultant neurotransmitter release. * Critical period A finite but modifiable developmental time window during which experience provides information that

is essential for normal development and permanently alters brain structure and performance. * Eye-blink conditioning A classical conditioning paradigm that is commonly used for the study of

learning. In it, an eye-blink, or the retraction of the nictitating membrane over the eye, is reflexively conditioned by pairing a conditioned neutral stimulus such as a tone with an

aversive stimulus such as an air-puff to the eye. After sufficient pairings the conditioned stimulus can elicit the eye-blink response by itself. * Memory consolidation A

protein-synthesis-dependent process of memory stabilization occuring over hours in animals and for up to years in humans that renders the memory resistant to change. * Amblyopia Poor vision,

usually occurring in one eye, that is associated with a prolonged period of indistinct visual stimulation or visual system dysfunction during development. * Ischaemic preconditioning (IPC).

A phenomenon observed both clinically and experimentally whereby a mild ischaemic event 'primes' a tissue by activating endogenous cellular protective mechanisms that amelioriate

the neurotoxic outcome of a later, more severe ischaemic event. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Abraham, W. Metaplasticity: tuning

synapses and networks for plasticity. _Nat Rev Neurosci_ 9, 387 (2008). https://doi.org/10.1038/nrn2356 Download citation * Issue Date: May 2008 * DOI: https://doi.org/10.1038/nrn2356 SHARE

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